Diamide compound and drugs containing the same

ABSTRACT

The present invention provides diamide derivatives represented by the following general formula (1):                    
     wherein A is a phenyl group or the like, which may be substituted, B is —CH═CH—, —C═C—, —(CH═CH) 2 —, —C≡C—CH═CH—, —CH═CH—C≡C—, phenylene or the like, and W is                    
     or                    
     and medicines comprising such a compound. These compounds have an excellent inhibitory effect on the production of an IgE antibody and are hence useful as antiallergic agents and the like.

This application is a national stage entry under 35 U.S.C. 371 ofPCT/JP97/02882, filed Aug. 20, 1997.

FIELD OF THE INVENTION

The present invention relates to novel diamide compounds and medicinesuseful in preventing and treating allergic immunological diseases,comprising such a compound as an active ingredient.

DESCRIPTION OF THE BACKGROUND

IgE, which is a kind of immunoglobulin (Ig), is an allergen-specificmolecule produced by an IgE producing cell differentiated from a B cell.This process is triggered by the contact of an immunocyte with anallergen in vivo.

IgE is produced in a target organ for an allergy and binds to a receptoron the surface of a mast cell, which is a central effector cell in anallergic reaction (sensitized state), or basophil. After thesensitization, allergic chemical mediators such as histamine,leukotrienes, prostaglandins and PAF, and injuring enzymes such astriptase are released from the mast cell stimulated by the reaction ofthe specific IgE and the allergen which invades in the living body, sothat immediate responses, such as vascular permeability acceleration,smooth muscle constriction, and vasodilation are elicited. Further,cytokines such as IL-4, which directly activate other immune systemcells, are also secreted from the stimulated mast cell. As a result,eosinophils, basophils and the like infiltrate into a tissue, and theallergic chemical mediators and tissue injuring proteins such as MBP,which are secreted by these inflammatory cells, induce a late response,so that the allergic symptom is lingered and taken seriously ill.

From this, IgE is considered a substance fundamentally participating inthe attack of an allergic immunological disease.

Therefore, several compounds having an inhibitory effect on theproduction of an IgE antibody have been found and reported to date witha view toward developing antiallergic agents [Pharmacology and Therapy,1994, 22(3), 1369; Japanese Patent Application Laid-Open No.106818/1989; Japanese Patent Publication No. 17506/1995; and JapanesePatent Application Laid-Open No. 92216/1996]. However, the object hasbeen not always sufficiently achieved under the circumstances.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to find a compoundhaving a strong inhibitory effect on the production of an IgE antibodyso as to provide a medicine effective for allergic immunologicaldiseases, comprising this compound as an active ingredient.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

With the foregoing circumstances in view, the present inventors havecarried out an extensive investigation. As a result, it has been foundthat novel diamide compounds represented by the general formula (1),which will be described subsequently, salts thereof, or hydrates orsolvates thereof have an excellent inhibitory effect on the productionof an IgE antibody and are useful for medicines such as antiallergicagents, thus leading to completion of the present invention.

According to the present invention, there is thus provided a compoundrepresented by the following general formula (1):

wherein

A is a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl,isoindolyl, quinolyl or isoquinolyl group which may be substituted;

B is a group of —CH═CH—, —C≡C—, —(CH═CH)₂—, —CH═CH—C≡C— or —C≡C—CH═CH—,or a divalent residue of benzene, pyridine, pyrimidine or pyrazine; and

W is a formula

or

in which X is

or

Y¹, Y² and Y³ are the same or different from one another and areindependently a hydrogen atom, —COOR¹ (R¹ is a hydrogen atom or a loweralkyl group), —CON(R²)R³ (R² and R³ are the same or different from eachother and are independently a hydrogen atom, or a hydroxyl or loweralkyl group), —CH₂—N(R⁴)R⁵ (R⁴ and R⁵ are the same or different fromeach other and are independently a hydrogen atom or a lower alkyl group,or R⁴ and R⁵ may form, together with the adjacent nitrogen atom, aheterocyclic ring which may further have an oxygen, nitrogen or sulfuratom), or —CH₂—S—R⁶ (R⁶ is a lower alkyl, phenyl or pyridyl group), orY¹ and Y² may couple to each other to form an alkylene group which maybe through an oxygen, a nitrogen or a sulfur, Z is a benzene or pyridinering, and n is an integer of 2 or 3, with the proviso that when B is ap-phenylene group, and W is a 1,4-piperazinyl group, A is not a phenylgroup, and when B is —CH═CH—, A is not a phenyl group which may besubstituted,

or a salt thereof, or a hydrate or solvate thereof.

According to the present invention, there is also provided a medicinecomprising the above compound as an active ingredient.

According to the present invention, there is further provided amedicinal composition comprising the above compound and apharmaceutically acceptable carrier.

According to the present invention, there is still further provided useof the above compound for a medicine.

According to the present invention, there is yet still further provideda method of treating an allergic immunological disease, which comprisesadministering an effective amount of the above compound.

BEST MODE FOR CARRYING OUT THE INVENTION

The amide compounds according to the present invention are representedby the general formula (1). In these compounds, the lower alkyl groupsinclude linear or branched alkyl groups having 1-8 carbon atoms.Specific examples thereof include methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octylgroups. Of these, those having 1-6 carbon atoms, for example, methyl,ethyl, propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl andn-hexyl groups, are particularly preferred.

The lower alkoxy groups include linear or branched alkoxy groups having1-8 carbon atoms. Specific examples thereof include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy,pentyloxy, hexyloxy, heptyloxy and octyloxy groups. Of these alkoxygroups, those having 1-6 carbon atoms are preferred.

The halogen atoms include fluorine, chlorine, bromine and iodine atoms.

In the formula (1), A is a phenyl, naphthyl, dihydronaphthyl, indenyl,pyridyl, indolyl, i-indolyl, quinolyl or i-quinolyl group. These groupsmay have 1-3 substituents. Here, examples of the substituents on thesegroups include a hydroxyl group, halogen atoms, lower alkyl groups whichmay be substituted by 1-3 halogen atoms, lower alkoxy groups, an aminogroup which may be substituted by one or two lower alkyl groups, andalkylthio groups.

Particularly preferable examples of A include tri-lower alkoxy-phenylgroups.

In B, examples of the substituent on the divalent residue of benzene,pyridine, pyrimidine or pyrazine include nitro, amino, lower alkyl andlower alkoxy groups, and halogen atoms.

More preferred as B is —CH═CH—, —C≡C—, —(CH═CH)₂—, —C≡C—CH═CH—,—CH═CH—C≡C—, or a divalent residue of benzene, pyridine, pyrimidine orpyrazine. Of these, —CH═CH—CH═CH—, —C≡C—CH═CH—, —CH═CH—C≡C— and abenzene residue (phenylene group) are particularly preferred.

In the general formula (1), preferable example of the heterocyclic ringwhich is formed by R⁴ and R⁵ together with the adjacent nitrogen atominclude those having 3-10 carbon atoms. Specific examples thereofinclude pyrrolidine, oxazole, isoxazole, thiazole, isothiazole,imidazole, imidazoline, imidazolidine, pyridine, piperidine, piperazine,morpholine and phthalimide. The alkylene group formed by bonding Y¹ andY² to each other preferably has 3-8 carbon atoms. Rings formed by thealkylene group which may be through an oxygen, a nitrogen or a sulfurinclude pyrrolidine, imidazolidine and piperazine. More preferred as Y¹,Y² and Y³ are a hydrogen atom, and carboxyl, aminomethyl, di-loweralkyl-amino and lower alkyl-aminomethyl groups, with a hydrogen atom,and carboxyl, aminomethyl, dimethylamino and dimethylaminomethyl groupsbeing particularly preferred.

Particularly preferred as W is piperazine or homopiperazine ring whichmay be substituted by a carboxyl, aminomethyl, di-lower alkyl-amino ordi-lower alkyl-aminomethyl group, or

Incidentally, in the general formula (1), A is not a phenyl group when Bis a p-phenylene group, and W is a 1,4-piperazinyl group. A is not aphenyl group which may be substituted when B is —CH═CH—.

The salts of the diamide compounds (1) may be any salts so far as theyare pharmaceutically acceptable salts. Examples thereof include mineralacid salts such as sulfates; organic acid salts such asmethanesulfonates, acetates, oxalates and citrates, and besides in thecase where the diamide compounds (1) are acidic compounds, alkali metalsalts such as sodium salts and potassium salts; alkaline earth metalsalts such as calcium salts and magnesium salts; and organic basic saltssuch as pyridine salts, picoline salts and triethylamine salts.

The diamide compounds (1) may be present in the form The diamidecompounds (1) can be prepared in accordance with, for example, thefollowing reaction formula:

More specifically, the compounds (1) according to the present inventionare obtained by the N-acylating reaction of a carboxylic acid (2) or areactive derivative thereof with an amine (3).

The N-acylating reaction may be conducted by using any N-acylatingreaction known per se in the art. It is particularly preferable toapply, for example, (a) a method in which the carboxylic acid (2) andthe amine (3) are reacted in the presence of a base and/or acondensation agent in a solvent, or (b) a method in which a reactivederivative of the carboxylic acid (2) and the amine (3) are reacted in asolvent.

Examples of the solvents used in these reactions may includedimethylformamide, tetrahydrofuran, dioxane, acetonitrile, methylenechloride and dichloroethane. Examples of the base may include organicbases such as pyridine, triethylamine and diisopropylethylamine, andinorganic bases such as sodium carbonate and sodium hydrogencarbonate.Examples of usable condensation agents include1,3-dicyclohexylcarbodiimide,1-cyclohexyl-3-morpholinoethylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1,1′-carbonyldiimidazole,diethyl phosphorocyanidate, diphenylphosphoryl azide,bis(2-oxo-3-oxazolidinyl)phosphinic chloride and2-chloro-1-methylpyridinium iodide. Examples of usable derivatives ofthe carboxylic acid include acid halides such as acid chlorides, acidazides, symmetric acid anhydrides, mixed anhydrides with pivalic acid orthe like, and active esters such as cyanomethyl esters and p-nitrophenylesters.

In each of the method (a) and the method (b), the N-acylating reactionis completed by reacting the carboxylic acid (2) or the reactivederivative thereof with the amine (3) at a reaction temperature of 0° C.to 100° C. for 30 minutes to 30 hours. The isolation and purification ofthe compound (1) from the reaction mixture may be conducted by using anymethods known per se in the art, for example, filtration, extraction,washing, drying, concentration, recrystallization and various kinds ofchromatography.

The compound (1) thus obtained may be converted into an acid-additionsalt in a method known per se in the art.

The compound may also be converted into a solvate with a solvent forreaction, a solvent for recrystallization, or the like, in particular, ahydrate.

Since the diamide compounds (1) according to the present invention havean excellent inhibitory effect on the production of an IgE antibody,they are useful as medicines for prevention and treatment of variousallergic immunological diseases, in which IgE participates, for example,asthma, atopic dermatitis, allergic rhinitis, inflammatory boweldiseases and contact dermatitis.

The diamide compounds (1) or the salts thereof can be formulated intovarious oral and parenteral preparations in the form of a solid,semisolid or liquid by adding a pharmaceutically acceptable carrier inaccordance with a method known per se in the art.

Examples of the oral preparations include tablets, pills, granules, softand hard capsules, powders, grains, triturations, emulsions, syrups,pellets and elixirs. Examples of the parenteral preparations includeinjections, drops, infusions, ointments, lotions, tonics, sprays,inhalation suspensions, oils, emulsions and suppositories. The activeingredients according to the present invention may be formulated intovarious preparations in accordance with a method known per se in theart. In these preparations, may be used surfactants, excipients,colorants, smell corrigents, preservatives, stabilizers, buffers,suspension stabilizers, isotonic agents and the like, as needed.

The dose of the diamide compound (1) or the salt thereof variesaccording to the kind of the compound, the kind of a disease to betreated or prevented, an administration method, the condition, age, sex,weight of a patient to be administered, treatment time, and the like.However, the compound may be administered in a dose of 0.01-1,000 mg/kg(weight)/day. The compound may be administered at once or in severalportions, for example, 2 to 6 portions a day.

EXAMPLES

The present invention will hereinafter be described in more detail bythe following Examples. However, the present invention is not limited tothese examples. Referential Example 1:

5-Phenylpenta-(2E,4E)-dienoic acid⁽¹⁾

(1) Saljoughian, M.; Williams, P. G., J. Org. Chem. 1987, 52, 3481-3483.

To a solution of 16 ml (72 mmol) of triethyl 4-phosphonocrotonate inanhydrous tetrahydrofuran (100 ml) was added 43 ml (69 mmol) of a 1.6 Mn-butyllithium solution dropwise with stirring in an ice-salt bath undernitrogen, and the mixture was stirred for 30 minutes. Then, 5.0 ml (49mmol) of benzaldehyde was added dropwise to this reaction mixture overabout 5 minutes, and the resultant mixture was stirred for 10 minutes inthe ice-salt bath and for an additional 3 hours at room temperature. Asaturated aqueous solution of ammonium chloride was added to thereaction mixture to conduct extraction with ether. An organic layer wasdried over anhydrous sodium sulfate and then concentrated under reducedpressure, and the resultant crude oil (15.9 g) was purified bychromatography on silica gel, thereby obtaining 8.14 g (yield: 82%) ofethyl 5-phenylpenta-(2E,4E)-dienoate.

Added to a solution of 8.14 g (40.3 mmol) of ethyl5-phenylpenta-(2E,4E)-dienoate synthesized by the above process inmethanol-tetrahydrofuran (40 ml-80 ml) was 40 ml of a 5N aqueoussolution of potassium hydroxide, and the mixture was stirred for 1 hourat room temperature. The reaction mixture was concentrated under reducedpressure, and the resultant residue was cooled in an ice bath. To itwere added 20 ml of chloroform and concentrated hydrochloric acid withvigorous stirring. An aqueous layer and an organic layer were separatedfrom each other, and the aqueous layer was further extracted withchloroform. The resultant organic layers were collected, dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The resultant crude oil was recrystallized from ethyl acetate-hexane topurify it, thereby obtaining 5.91 g (yield: 84%) of the title compound.

Example 1

Preparation of 1,4-bis[5-phenylpenta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

After 2.49 g (14.3 mmol) of 5-phenylpenta-(2E,4E)-dienoic acid wereadded to a solution of 653 mg (6.51 mmol) of homopiperazine in anhydrousdimethylformamide (30 ml), a reaction vessel was transferred to an icebath, and 2.7 ml (19 mmol) of triethylamine and 3.0 ml (14 mmol) ofdiphenylphosphorylazide were added and the resultant mixture was stirredfor 1 hour. Added to the reaction mixture was 40 ml of a 5% aqueoussolution of sodium hydrogencarbonate to conduct extraction withchloroform. An organic layer was dried over anhydrous sodium sulfate andthen concentrated under reduced pressure. The resultant crude oil (8.4g) was purified by column chromatography on alumina and columnchromatography on silica gel, and then recrystallized from ethylacetate-hexane, thereby obtaining 2.18 g (yield: 81%) of the titlecompound as a colorless crystalline powder.

Melting point: 155-156° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.81(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0Hz,4H), 3.70(s,4H), 6.63(d,J=14.6 Hz,2H), 6.90(d,J=15.6 Hz,2H),7.02(dd,J=15.6,10.3 Hz,2H), 7.23(dd,J=14.6,10.3 Hz,2H), 7.23-7.37(m,6H),7.44-7.49(m,4H).

Example 2

Preparation of1,4-bis[5-(2-methoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 223 mg (yield: 97%)of the title compound was obtained as a colorless amorphous powder from200 mg (0.98 mmol) of 5-(2-methoxyphenyl)penta-(2E,4E)-dienoic acid and49 mg (0.49 mmol) of homopiperazine.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.81(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0Hz,4H), 3.68(s,4H), 3.83(s,6H), 6.58(d,J=14.5 Hz,2H),6.92(ddd,J=7.4,7.4,1.0 Hz,2H), 6.97-7.13(m,4H), 7.00(dd,J=8.4,1.0Hz,2H), 7.23(ddd,J=14.5,9.0,1.5 Hz,2H), 7.25(ddd,J=8.4,7.4,1.7 Hz,2H),7.48(dd,J=7.4,1.7 Hz,2H).

Example 3

Preparation of1,4-bis[5-(3-trifluoromethylphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 216 mg (yield: 94%)of crude crystals of the title compound were obtained from 202 mg (0.84mmol) of 5-(3-trifluoro-methylphenyl)penta-(2E,4E)-dienoic acid and 42mg (0.42 mmol) of homopiperazine. The crude crystals thus obtained wererecrystallized from chloroform-hexane, thereby obtaining a colorlesscrystalline powder.

Melting point: 181-182° C.

¹H-NMR (CDCl₃) (mixture of amide rotamers) δ: 1.90-2.05(m,2H),3.56-3.88(m,4H), 3.80(s,4H), 6.48(br d,J=14.5 Hz,1.3H), 6.50(br d,J=14.5Hz,0.7H), 6.82-7.09(m,4H), 7.40-7.73(m,10H).

Example 4

Preparation of1,4-bis[5-(3-methoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 133 mg (yield: 62%)of the title compound was obtained as a pale yellow amorphous powderfrom 186 mg (0.91 mmol) of 5-(3-methoxyphenyl)penta-(2E,4E)-dienoic acidand 46 mg (0.46 mmol) of homopiperazine.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.81(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0Hz,4H), 3.69(s,4H), 3.78(s,6H), 6.63(d,J=14.8 Hz,2H),6.85(ddd,J=8.1,2.6,0.9 Hz,2H), 6.87(d,J=15.1 Hz,2H), 7.02(dd,J=15.1,10.5Hz,2H), 6.99-7.09(m,4H), 7.23(dd,J=14.8,10.5 Hz,2H), 7.24(dd,J=8.1,8.1Hz,2H).

Example 5

Preparation of1,4-bis[5-(4-fluorophenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 217 mg (yield: 94%)of the title compound was obtained as a colorless amorphous powder from202 mg (1.1 mmol) of 5-(4-fluorophenyl)penta-(2E,4E)-dienoic acid and 47mg (0.47 mmol) of homopiperazine. The amorphous powder thus obtained wasrecrystallized from methanol-chloroform-hexane, thereby obtaining acolorless crystalline powder.

Melting point: 230-231° C.

¹H-NMR (CD₃OD—CDCl₃) (mixture of amide rotamers) δ: 1.90-2.05(m,2H),3.55-3.75(m,4H), 3.78(s,4H), 6.43(br d,J=14.5 Hz,1.3H), 6.47(br d,J=14.5Hz,0.7H), 6.82-6.91(m,4H), 7.06(dd,J=8.7,³J_(HF)=8.7 Hz,4H),7.35-7.55(m,6H).

Example 6

Preparation of1,4-bis[5-(4-trifluoromethylphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 217 mg (yield: 79%)of the title compound was obtained as a colorless amorphous powder from242 mg (1.0 mmol) of 5-(4-trifluoromethylphenyl)penta-(2E,4E)-dienoicacid and 51 mg (0.51 mmol) of homopiperazine. The amorphous powder thusobtained was recrystallized from methanol-chloroform-hexane, therebyobtaining colorless needles.

Melting point: 233-235° C.

¹H-NMR (CDCl₃) (mixture of amide rotamers) δ: 2.00(br tt,J=6.1,6.1Hz,2H), 3.58-3.82(m,8H), 6.48(d,J=6.7 Hz,1.3H), 6.52(d,J=6.7 Hz,0.7H),6.84-7.04(m,4H), 7.41-7.64(m,10H).

Example 7

Preparation of1,4-bis[5-(4-tert-butylphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 410 mg (yield: 78%)of the title compound was obtained as a colorless amorphous powder from460 mg (2.0 mmol) of 5-(4-tert-butylphenyl)penta-(2E,4E)-dienoic acidand 100 mg (1.0 mmol) of homopiperazine. The amorphous powder thusobtained was recrystallized from ethyl acetate-hexane, thereby obtainingcolorless needles.

Melting point: 162-164° C.

¹H-NMR (CDCl₃) (mixture of amide rotamers) δ: 1.32(s,18H),1.90-2.07(m,2H), 3.58-3.82(m,8H), 6.39(d,J=14.7 Hz,1.3H), 6.42(d,J=14.7Hz,0.7H), 6.81-6.92(m,4H), 7.29-7.60(m,10H).

Example 8

Preparation of1,4-bis[5-(4-chlorophenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 122 mg (yield: 65%)of the title compound was obtained as a colorless crystalline powderfrom 197 mg (0.94 mmol) of 5-(4-chlorophenyl)penta-(2E,4E)-dienoic acidand 39 mg (0.39 mmol) of homopiperazine.

Melting point: 248-250° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.80(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0Hz,4H), 3.69(s,4H), 6.63(d,J=14.6 Hz,2H), 6.88(d,J=15.5 Hz,2H),7.02(dd,J=15.5,10.4 Hz,2H), 7.21(dd,J=14.6,10.4 Hz,2H), 7.35(d,J=8.6Hz,4H), 7.48(d,J=8.6 Hz,4H).

Example 9

Preparation of1,4-bis[5-(4-di-n-butylaminophenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepinedihydrochloride:

In accordance with the same process as in Example 1, 161 mg (yield: 79%)of1,4-bis[5-(4-di-n-butylaminophenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepinewas obtained as a yellow oil from 192 mg (0.64 mmol) of5-(4-di-n-butylaminophenyl)penta-(2E,4E)-dienoic acid and 31 mg (0.31mmol) of homopiperazine. Added to a solution of 130 mg of thethus-obtained yellow oil in ethanol (5 ml) was 0.5 ml of 1N hydrochloricacid, and the resultant mixture was concentrated under reduced pressure.Thereafter, ether was added, thereby obtaining the title compound as ayellow amorphous powder.

¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ: 0.91(t,J=7.4Hz,12H), 1.33(tq,J=7.4,7.4 Hz,8H), 1.53(tt,J=7.4,7.4 Hz,8H), 1.80(brtt,J=5.9,5.9 Hz,2H), 3.30(t,J=7.4 Hz,8H), 3.56(br dd,J=5.9,5.9 Hz,4H),3.67(s,4H), 6.47(d,J=14.7 Hz,2H), 6.70-6.81(m,4H), 6.77(d,J=8.6 Hz,4H),7.16-7.32(m,2H), 7.32(d,J=8.6 Hz,4H).

Example 10

Preparation of1,4-bis[5-(4-methoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, crude crystals wereobtained from 200 mg (0.98 mmol) of5-(4-methoxyphenyl)penta-(2E,4E)-dienoic acid and 49 mg (0.49 mmol) ofhomopiperazine. The thus-obtained crude crystals were recrystallizedfrom chloroform-hexane, thereby obtaining 213 mg (yield: 92%) of thetitle compound as a colorless crystalline powder.

Melting point: 210-212° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.80(tt,J=6.0,6.0 Hz,2H), 3.57(dd,J=6.0,6.0Hz,4H), 3.68(s,4H), 3.78(s,6H), 6.55(d,J=14.7 Hz,2H), 6.80-6.95(m,4H),6.90(d,J=8.9 Hz,4H), 7.21(ddd,J=14.7,7.5,2.7 Hz,2H), 7.41(d,J=8.9Hz,4H).

Example 11

Preparation of1,4-bis[5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 194 mg(quantitative) of the title compound was obtained as a colorlessamorphous powder from 204 mg (0.87 mmol) of5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 37 mg (0.37 mmol)of homopiperazine.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.81(tt,J=6.0,6.0 Hz,2H), 3.57(dd,J=6.0,6.0Hz,4H), 3.68(s,4H), 3.83(s,12H), 6.50(d,J=14.2 Hz,2H), 6.65(d,J=8.4Hz,4H), 7.07(d,J=15.3 Hz,2H), 7.19(dd,J=14.2,10.6 Hz,2H), 7.20(t,J=8.4Hz,2H), 7.29(dd,J=15.3,10.6 Hz,2H).

Example 12

Preparation of1,4-bis[5-(2,4-dimethoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 170 mg (yield: 73%)of the title compound was obtained as a colorless amorphous powder from206 mg (0.88 mmol) of 5-(2,4-dimethoxyphenyl)penta-(2E,4E)-dienoic acidand 44 mg (0.44 mmol) of homopiperazine.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.80(tt,J=5.9,5.9 Hz,2H), 3.56(dd,J=5.9,5.9Hz,4H), 3.67(s,4H), 3.79(s,6H), 3.83(s,6H), 6.50(d,J=14.6 Hz,2H),6.52(dd,J=8.5,2.3 Hz,2H), 6.56(d,J=2.3 Hz,2H), 6.90(dd,J=15.6,9.8Hz,2H), 7.00(d,J=15.6 Hz,2H), 7.20(dd,J=14.6,9.8 Hz,2H), 7.40(d,J=8.5Hz,2H).

Example 13

Preparation of1,4-bis[5-(4-tert-butyl-2-methoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 238 mg (yield: 91%)of the title compound was obtained as a pale yellow amorphous powderfrom 234 mg (0.90 mmol) of5-(4-tert-butyl-2-methoxyphenyl)penta-(2E,4E)-dienoic acid and 45 mg(0.45 mmol) of homopiperazine.

¹H-NMR (DMSO-d₆, 120° C.) δ:

1.30(s,18H), 1.80(tt,J=6.0,6.0 Hz,2H), 3.57(dd,J=6.0,6.0 Hz,4H),3.68(s,4H), 3.84(s,6H), 6.55(d,J=14.5 Hz,2H), 6.93-7.12(m,8H),7.22(ddd,J=14.5,8.6,1.6 Hz,2H), 7.40(d,J=7.8 Hz,2H).

Example 14

Preparation of1,4-bis[5-(3,4-dimethoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 182 mg (yield: 83%)of the title compound was obtained as a colorless amorphous powder from217 mg (0.82 mmol) of 5-(3,4-dimethoxyphenyl)penta-(2E,4E)-dienoic acidand 41 mg (0.41 mmol) of homopiperazine.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.81(tt,J=5.8,5.8 Hz,2H), 3.58(dd,J=5.8,5.8Hz,4H), 3.68(s,4H), 3.78(s,6H), 3.80(s,6H), 6.55(d,J=14.6 Hz,2H),6.81(d,J=15.8 Hz,2H), 6.91(dd,J=15.8,9.9 Hz,2H), 6.91(d,J=8.4 Hz,2H),7.02(dd,J=8.4,2.1 Hz,2H), 7.10(d,J=2.1 Hz,2H), 7.21(dd,J=14.6,9.9Hz,2H).

Example 15

Preparation of1,4-bis[5-(3,5-dimethoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 186 mg (yield: 95%)of the title compound was obtained as a colorless amorphous powder from207 mg (0.83 mmol) of 5-(3,5-dimethoxyphenyl)penta-(2E,4E)-dienoic acidand 37 mg (0.37 mmol) of homopiperazine.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.81(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0Hz,4H), 3.68(s,4H), 3.76(s,12H), 6.43(t,J=2.2 Hz,2H), 6.63(d,J=14.5Hz,2H), 6.65(d,J=2.2 Hz,4H), 6.82(d,J=15.4 Hz,2H), 7.01(dd,J=15.4,10.7Hz,2H), 7.21(dd,J=14.5,10.7 Hz,2H).

Example 16

Preparation of1,4-bis[5-(2,4,6-trimethoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, crude crystals wereobtained from 211 mg (0.80 mmol) of5-(2,4,6-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 41 mg (0.41mmol) of homopiperazine. The crude crystals were recrystallized fromethanol-ether, thereby obtaining 177 mg (yield: 75%) of the titlecompound as a pale yellow crystalline powder.

Melting point: 190-195° C.

¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

1.80(br tt,J=6.0,6.0 Hz,2H), 3.56(br dd,J=6.0,6.0 Hz,4H), 3.66(br s,4H),3.80(s,6H), 3.82(s,12H), 6.24(s,4H), 6.36-6.47(m,2H), 6.94-7.07(m,2H),7.10-7.24(m,4H).

Example 17

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, crude crystals of146 mg (quantitative) of the title compound were obtained from 157 mg(0.60 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and25 mg (0.25 mmol) of homopiperazine. The thus-obtained crude crystalswere recrystallized from ethanol, thereby obtaining pale yellow needles.

Melting point: 147-149° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.81(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0Hz,4H), 3.69(s,4H), 3.72(s,6H), 3.81(s,12H), 6.60(d,J=14.7 Hz,2H),6.80(s,4H), 6.81(d,J=15.4 Hz,2H), 6.97(dd,J=15.4,10.5 Hz,2H),7.21(dd,J=14.7,10.5 Hz,2H).

Example 18

Preparation of1,4-bis[5-(3,5-dimethoxy-4-isopropoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 222 mg (yield: 93%)of the title compound was obtained as a colorless amorphous powder from220 mg (0.37 mmol) of5-(3,5-dimethoxy-4-isopropoxyphenyl)penta-(2E,4E)-dienoic acid and 37 mg(0.37 mmol) of homopiperazine.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.20(d,J=6.2 Hz,12H), 1.81(tt,J=5.9,5.9Hz,2H), 3.58(dd,J=5.9,5.9 Hz,4H), 3.69(s,4H), 3.79(s,12H),4.33(qq,J=6.2,6.2 Hz,2H), 6.59(d,J=14.7 Hz,2H), 6.80(s,4H),6.82(d,J=15.5 Hz,2H), 6.97(dd,J=15.5,10.6 Hz,2H), 7.22(dd,J=14.7,10.6Hz,2H).

Example 19

Preparation of1,4-bis[5-(2-pyridyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, crude crystals wereobtained from 230 mg (1.1 mmol) of 5-(2-pyridyl)penta-(2E,4E)-dienoicacid and 49 mg (0.49 mmol) of homopiperazine. The crude crystals wererecrystallized from chloroform-ether, thereby obtaining 193 mg (yield:95%) of the title compound as a colorless crystalline powder.

Melting point: 196-197° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.81(tt,J=6.0,6.0 Hz,2H), 3.59(dd,J=6.0,6.0Hz,4H), 3.70(s,4H), 6.74(d,J=14.6 Hz,2H), 6.93(d,J=15.1 Hz,2H),7.21(ddd,J=7.6,4.8,1.0 Hz,2H), 7.25(dd,J=14.6,11.3 Hz,2H),7.42(dd,J=15.1,11.3 Hz,2H), 7.42(br d,J=7.6 Hz,2H),7.71(ddd,J=7.6,7.6,1.8 Hz,2H), 8.52(br d,J=4.8 Hz,2H).

Example 20

Preparation of1,4-bis[5-(3-pyridyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, crude crystals of207 mg (yield: 97%) of the title compound were obtained from 240 mg (1.1mmol) of 5-(3-pyridyl)penta-(2E,4E)-dienoic acid and 52 mg (0.52 mmol)of homopiperazine. The thus-obtained crude crystals were recrystallizedfrom ethanol-ether, thereby obtaining a colorless crystalline powder.

Melting point: 221-222° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.81(tt,J=6.0,6.0 Hz,2H), 3.59(dd,J=6.0,6.0Hz,4H), 3.70(s,4H), 6.67(d,J=13.9 Hz,2H), 6.92(d,J=15.1 Hz,2H),7.12(dd,J=15.1,10.6 Hz,2H), 7.23(dd,J=13.9,10.6 Hz,2H),7.32(dd,J=7.9.4.8 Hz,2H), 7.85(ddd,J=7.9,2.2,1.6 Hz,2H),8.44(dd,J=4.8,1.6 Hz,2H), 8.66(d,J=2.2 Hz,2H).

Example 21

Preparation of1,4-bis[5-(2-methylthiopyridin-3-yl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, crude crystals of214 mg (yield: 98%) of the title compound were obtained from 191 mg(0.87 mmol) of 5-(2-methylthiopyridin-3-yl)penta-(2E,4E)-dienoic acidand 43 mg (0.43 mmol) of homopiperazine. The thus-obtained crudecrystals were recrystallized from ethanol-ether, thereby obtaining acolorless crystalline powder.

Melting point: 182-184° C.

¹H-NMR (DMSO-d₆, 120° C.) δ:

1.80(tt,J=6.0,6.0 Hz,2H), 2.53(s,6H), 3.59(dd,J=6.0,6.0 Hz,4H),3.69(s,4H), 6.67(d,J=14.7 Hz,2H), 6.93-7.13(m,4H), 7.08(dd,J=7.8,4.6Hz,2H), 7.23(ddd,J=14.7,8.5,1.6 Hz,2H), 7.78(dd,J=7.8,1.7 Hz,2H),8.36(dd,J=4.6,1.7 Hz,2H).

Example 22

Preparation of1,4-bis[5-(2,6-dimethoxypyridin-3-yl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, crude crystals of220 mg (yield: 99%) of the title compound were obtained from 194 mg(0.83 mmol) of 5-(2.6-dimethoxypyridin-3-yl)penta-(2E,4E)-dienoic acidand 42 mg (0.42 mmol) of homopiperazine. The thus-obtained crudecrystals were recrystallized from chloroform-ether, thereby obtaining apale yellow crystalline powder.

Melting point: 227-230° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.79(tt,J=6.0,6.0 Hz,2H), 3.56(dd,J=6.0,6.0Hz,4H), 3.67(s,4H), 3.89(s,6H), 3.96(s,6H), 6.35(d,J=8.1 Hz,2H),6.51(d,J=14.5 Hz,2H), 6.87(br d,J=15.5 Hz,2H), 6.96(dd,J=15.5,9.4Hz,2H), 7.19(ddd,J=14.5,9.4,0.9 Hz,2H), 7.76(d,J=8.1 Hz,2H).

Example 23

Preparation of1,4-bis[5-(3-quinolyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, crude crystals wereobtained from 180 mg (0.84 mmol) of 5-(3-quinolyl)penta-(2E,4E)-dienoicacid and 38 mg (0.38 mmol) of homopiperazine. The crude crystals wererecrystallized from methanol, thereby obtaining 124 mg (yield: 63%) ofthe title compound as colorless needles.

Melting point: 222-223° C.

¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:1.84(tt,J=6.0,6.0 Hz,2H), 3.62(dd,J=6.0,6.0 Hz,4H), 3.73(s,4H),6.67-6.79(m,2H), 7.04-7.16(m,2H), 7.24-7.37(m,4H),7.55(ddd,J=8.3,7.0,1.1 Hz,2H), 7.69(ddd,J=8.3,7.0,1.5 Hz,2H), 7.87(brd,J=8.3 Hz,2H), 7.96(br d,J=8.3 Hz,2H), 8.31(br d,J=2.0 Hz,2H),9.04(d,J=2.0 Hz,2H).

Example 24

Preparation of1,4-bis[5-(4-quinolyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 124 mg (yield: 34%)of the title compound was obtained as a pale brown amorphous powder from347 mg (1.5 mmol) of 5-(4-quinolyl)penta-(2E,4E)-dienoic acid and 70 mg(0.70 mmol) of homopiperazine.

¹H-NMR (CDCl₃) (mixture of amide rotamers) δ: 1.75-2.15(m,2H),3.60-3.90(m,8H), 6.58(d,J=14.7 Hz,1.3H), 6.62(d,J=14.7 Hz,0.7H),7.07-7.22(m,2H), 7.47-7.78(m,10H), 8.00-8.20(m,4H), 8.90(d,J=4.4Hz,1.3H), 8.90(d,J=4.4 Hz,0.7H).

Example 25

Preparation of1,4-bis[5-(8-quinolyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 1, 248 mg (yield: 69%)of the title compound was obtained as a pale yellow amorphous powderfrom 330 mg (1.5 mmol) of 5-(8-quinolyl)penta-(2E,4E)-dienoic acid and70 mg (0.70 mmol) of homopiperazine.

¹H-NMR (CDCl₃) (mixture of amide rotamers) δ: 1.97-2.12(m,2H),3.58-3.88(m,8H), 6.50(br d,J=14.7 Hz,1.5H), 6.53(br d,J=14.7 Hz,0.5H),7.22-7.40(m,2H), 7.44(br dd,J=8.1,4.2 Hz,2H), 7.55(br dd,J=7.8,7.8Hz,2H), 7.61-7.85(m,2H), 7.78(br d,J=7.8 Hz,2H), 7.97(br d,J=7.8 Hz,2H),8.08-8.26(m,2H), 8.16(br d,J=8.1 Hz,2H), 8.97(br s,2H).

Example 26

Preparation of1,4-bis[5-(3-methoxyphenyl)penta-(2E,4E)-dienoyl]piperazine:

In accordance with the same process as in Example 1, crude crystals of304 mg (yield: 94%) of the title compound were obtained from 300 mg (1.5mmol) of 5-(3-methoxyphenyl)penta-(2E,4E)-dienoic acid and 60 mg (0.70mmol) of piperazine. The thus-obtained crude crystals wererecrystallized from chloroform-ether, thereby obtaining colorlessneedles.

Melting point: 175-177° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 3.62(s,8H), 3.79(s,6H), 6.68(d,J=14.6Hz,2H), 6.86(ddd,J=1.2,2.2,8.1 Hz,2H), 6.90(d,J=15.5 Hz,2H),7.03(dd,J=10.3,15.5 Hz,2H), 7.03-7.11(m,4H), 7.25(dd,J=10.3,14.6 Hz,2H),7.26(dd,J=8.1,8.1 Hz,2H).

Example 27

Preparation of1,4-bis[5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazine:

In accordance with the same process as in Example 1, crude crystals wereobtained from 172 mg (0.87 mmol) of5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 31 mg (0.37 mmol)of piperazine. The crude crystals were recrystallized fromchloroform-ether-hexane, thereby obtaining 145 mg (yield: 77%) of thetitle compound as a colorless crystalline powder.

Melting point: at least 270° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 3.61(s,8H), 3.84(s,12H), 6.55(d,J=14.2Hz,2H), 6.67(d,J=8.4 Hz,4H), 7.10(d,J=15.4 Hz,2H), 7.21(t,J=8.4 Hz,2H),7.22(dd,J=14.2,10.7 Hz,2H), 7.31(dd,J=15.4,10.7 Hz,2H).

Example 28

Preparation of1,4-bis[5-(4-tert-butyl-2-methoxyphenyl)penta-(2E,4E)-dienoyl]piperazine:

In accordance with the same process as in Example 1, crude crystals wereobtained from 234 mg (0.90 mmol) of5-(4-tert-butyl-2-methoxyphenyl)penta-(2E,4E)-dienoic acid and 39 mg(0.45 mmol) of piperazine. The crude crystals were recrystallized fromethanol-ether, thereby obtaining 171 mg (yield: 66%) of the titlecompound as a colorless crystalline powder.

Melting point: 200-204° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.30(s,18H), 3.61(s,8H), 3.86(s,6H),6.60(d,J=14.5 Hz,2H), 6.95-7.07(m,8H), 7.25(ddd,J=14.5,9.2,1.0 Hz,2H),7.42(d,J=9.2 Hz,2H).

Example 29

Preparation of 1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E, 4E)-dienoyl]piperazine:

In accordance with the same process as in Example 1, crude crystals of141 mg (yield: 80%) of the title compound were obtained from 161 mg(0.61 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and37 mg (0.43 mmol) of piperazine. The thus-obtained crude crystals wererecrystallized from methanol-ether-chloroform, thereby obtaining paleyellow needles.

Melting point: 207-210° C.

¹H-NMR (CDCl₃) (mixture of amide rotamers) δ: 3.55-3.85(m,8H),3.87(s,6H), 3.90(s,12H), 6.46(d,J=14.4 Hz,2H), 6.69(s,4H),6.75-6.95(m,4H), 7.49(br dd,J=14.4,6.2 Hz,1H), 7.51(br dd,J=14.4,6.2Hz,1H).

Example 30

Preparation of 1,4-bis[5- (3,5-dimethoxy-4-isopropoxyphenyl)penta-(2E,4E) -dienoyl]piperazine:

In accordance with the same process as in Example 1, crude crystals wereobtained from 193 mg (0.66 mmol) of5-(3,5-dimethoxy-4-isopropoxyphenyl)penta-(2E,4E)-dienoic acid and 29 mg(0.33 mmol) of piperazine. The crude crystals were recrystallized fromethanol-ether-hexane, thereby obtaining 167 mg (yield: 81%) of the titlecompound as colorless flakes.

Melting point: 196-199° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.20(d,J=6.1 Hz,12H), 3.62(s,8H),3.80(s,12H), 4.33(qq,J=6.1,6.1 Hz,2H), 6.64(d,J=14.7 Hz,2H), 6.81(s,4H),6.84(d,J=15.4 Hz,2H), 6.97(dd,J=15.4,10.3 Hz,2H), 7.25(dd,J=14.7,10.3Hz,2H).

Example 31

Preparation of 1,4-bis[5-(4-quinolyl)penta-(2E,4E)-dienoyl]piperazine:

In accordance with the same process as in Example 1, 171 mg (yield: 48%)of the title compound were obtained as colorless amorphous powder from331 mg (1.5 mmol) of 5-(4-quinolyl)penta-(2E,4E)-dienoic acid and 60 mg(0.70 mmol) of piperazine.

¹H-NMR (CDCl₃) δ: 3.60-3.92(m,8H), 6.60(d,J=14.6 Hz,2H),7.15(dd,J=15.4,10.7 Hz,2H), 7.54(d,J=4.6 Hz,2H), 7.58-7.69(m,4H),7.65(br dd,J=7.1,7.1 Hz,2H), 7.76(ddd,J=8.5,7.1,1.5 Hz,2H),8.13(dd,J=7.1,1.5 Hz,2H), 8.14(dd,J=8.5,1.5 Hz,2H), 8.91(d,J=4.6 Hz,2H).

Example 32

Preparation of 1,4-bis[5-(8-quinolyl)penta-(2E,4E)-dienoyl]piperazine:

In accordance with the same process as in Example 1, 168 mg (yield: 56%)of the title compound was obtained as a pale yellow amorphous powderfrom 284 mg (1.3 mmol) of 5-(8-quinolyl)penta-(2E,4E)-dienoic acid and53 mg (0.60 mmol) of piperazine.

¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ: 3.68(m,8H),6.67-6.84(m,2H), 7.34-7.52(m,4H), 7.53(dd,J=8.3,4.2 Hz,2H),7.60(dd,J=8.1,7.5 Hz,2H), 7.90(d,J=8.1 Hz,2H), 7.93-8.16(m,2H),8.04(d,J=7.5 Hz,2H), 8.32(dd,J=8.3,1.9 Hz,2H), 8.95(dd,J=4.2,1.9 Hz,2H).

Example 33

Preparation of ethyl1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazine-2-carboxylate:

A suspension of 231 mg (1.0 mmol) of ethyl piperazine-2-carboxylatedihydrochloride⁽¹⁾ in anhydrous dimethylformamide (4 ml) was cooled inan ice bath. To the suspension were added 0.84 ml (6.0 mmol) oftriethylamine, 582 mg (2.2 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid, and 0.33 ml (2.2mmol) of diethyl phosphorocyanidate. The ice bath was removed, and themixture was stirred for 1 hour at room temperature. Added to thereaction mixture were 4 ml of a 5% aqueous solution of sodiumhydrogencarbonate to conduct extraction with chloroform. An organiclayer was dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure. The resultant crude oil (600 mg) was purified bycolumn chromatography on alumina and column chromatography on silica gelto obtain 511 mg (yield: 79%) of the title compound as a pale yellowamorphous powder.

(1) Jucker, von E.; Rissi, E., Helvetica Chim. Acta, 1962, 2383-2402.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.19(t,J=7.3 Hz,3H), 3.05-3.19(m,1H),3.25-3.48(m,2H), 3.73(s,6H), 3.82(s,12H), 4.04-4.21(m,2H), 4.12(q,J=7.3Hz,2H), 4.54-4.63(m,1H), 5.03-5.08(m,1H), 6.61(d,J=14.7 Hz,1H),6.64(d,J=14.7 Hz,1H), 6.82(s,4H), 6.85(d,J=15.6 Hz,1H), 6.87(d,J=15.6Hz,1H), 6.98(dd,J=15.6,10.0 Hz,2H), 7.24(dd,J=14.7,10.0 Hz,1H),7.27(dd,J=14.7,10.0 Hz,1H).

Example 34

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazine-2-carboxylicacid:

Added to a solution of 339 mg (0.52 mmol) of ethyl1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazine-2-carboxylatesynthesized by the process of Example 33 in methanol-tetrahydrofuran (1ml-1.5 ml) was 0.50 ml (1.5 mmol) of a 3N aqueous solution of potassiumhydroxide, and the mixture was stirred for 1 hour at room temperature. Asaturated saline solution (3 ml) and 1N hydrochloric acid (2 ml) wereadded to the reaction mixture to conduct extraction with chloroform. Anorganic layer was dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resultant crude oil (356 mg)was purified by column chromatography on silica gel to obtain 325 mg(quantitative) of the title compound as a pale yellow amorphous powder.

The amorphous powder was recrystallized from ethyl acetate-ethyl etherto obtain a pale yellow crystalline powder.

Melting point: 212° C. (decomposed).

¹H-NMR (DMSO-d₆, 120° C.) (no OH proton of the carboxyl group wasobserved) δ: 2.98-3.12(m,1H), 3.25-3.42(m,2H), 3.72(s,6H), 3.82(s,12H),4.02-4.23(m,2H), 4.56-4.65(m,1H), 4.80-4.90(m,1H), 6.62(d,J=14.7 Hz,1H),6.65(d,J=14.7 Hz,1H), 6.82(s,2H), 6.83(s,2H), 6.83(d,J=15.4 Hz,1H),6.84(d,J=15.4 Hz,1H), 6.97(dd,J=15.4,10.4 Hz,1H), 6.98(dd,J=15.4,10.4Hz,1H), 7.22(dd,J=14.7,10.4 Hz,1H), 7.24(dd,J=14.7,10.4 Hz,1H).

Example 35

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-N-methylpiperazine-2-carbohydroxamicacid:

Added to a solution of 148 mg (0.24 mmol) of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-piperazine-2-carboxylicacid synthesized by the process of Example 34 in anhydrousdimethylformamide (0.5 ml) was 44.9 mg (0.28 mmol) of1,1′-carbonyldiimidazole. After the mixture was stirred for 15 minutes,24.9 mg (0.30 mmol) of N-methylhydroxyamine hydrochloride and 0.050 ml(0.36 mmol) of triethylamine were added, and the mixture was stirred foran additional 15 minutes. Added to the reaction mixture was 3 ml of 0.5Nhydrochloric acid to conduct extraction with chloroform. An organiclayer was dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure. The resultant crude oil (179 mg) was purified bycolumn chromatography on silica gel to obtain 134.6 mg (yield: 87%) ofthe title compound as pale yellow amorphous powder.

¹H-NMR (CDCl₃) (mixture of amide rotamers; no OH proton was observed) δ:2.85(br s,3H), 3.15-4.05(m,4H), 3.87(s,9H), 3.91(s,9H), 4.40-4.85(m,2H),5.35-5.60(m,1H), 6.35-6.60(m,2H), 6.69(s,4H), 6.65-6.95(m,4H),7.40-7.60(m,2H).

Referential Example 2

Preparation of 2-(N,N-dimethylaminomethyl)piperazinetrihydrochloride⁽²⁾:

(2) Miyamoto, T.; Matsumoto, J.; Chiba, K.; Egawa, H.; Shibamori, K.;Minamide, A.; Nishimura, Y.; Okada, H.; Kataoka, M.; Fujita, M.; Hirose,T.; Nakano, J., J. Med. Chem., 1990, 33, 1465-1656.

A solution of 5.2 g (17 mmol) of1,4-benzyl-2-hydroxymethyl)piperazine⁽¹⁾ in anhydrous methylene chloride(45 ml) was cooled in an ice bath. To the solution was added 1.6 ml (21mmol) of methanesulfonyl chloride with stirring. The ice bath wasremoved, and the mixture was stirred for 13 hours at room temperature.Added to the reaction mixture were 40 ml of a 5% aqueous solution ofsodium hydrogencarbonate to conduct extraction with methylene chloride.An organic layer was dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resultant crude oil (4.7 g) wasdissolved in anhydrous dimethylformamide (15 ml). To the solution wereadded 3.0 g (38 mmol) of dimethylamine hydrochloride, 5.2 g (38 mmol) ofpotassium carbonate, and 6.2 g (38 mmol) of potassium iodide, and theresultant mixture was stirred f or 5 hours at 50° C. Water was added tothe reaction mixture to conduct extraction with chloroform. An organiclayer was dried over anhydrous sodium sulfate, an d then concentratedunder reduced pressure. The resultant crude oil was purified by columnchromatography on alumina and column chromatography on silica gel toobtain 3.2 g (yield: 67%) of1,4-dibenzyl-2-(N,N-dimethyl-aminomethyl)piperazine as a colorless oil.

(1) Jucker, von E.; Rissi, E., Helvetica Chim. Acta, 1962, 2383-2402.

Added to a solution of 3.1 g (10 mmol) of1,4-benzyl-2-(N,N-dimethylaminomethyl) piperazine synthesized by theabove process in methanol (25 ml) were 5 ml (60 mmol) of concentratedhydrochloric acid and 0.50 g of 10% palladium on carbon. The resultantmixture was stirred for 14 hours at 55° C. under hydrogen. To thereaction mixture was added 12 ml of water, and the catalyst was removedby suction filtration through Celite. The filtrate was concentratedunder reduced pressure, thereby obtaining 2.4 g (yield: 99%) of thetitle compound as a colorless crystalline powder.

Melting point: 265° C. (decomposed).

Example 36

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)piperazinehydrochloride:

In accordance with the same process as in Example 33, 371 mg (yield:58%) of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)piperazinewas obtained as a pale yellow amorphous powder from 528 mg (2.0 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 252 mg (1.0mmol) of 2-(N,N-dimethylaminomethyl)piperazine trihydrochloridesynthesized by the process described in Referential Example 2. Added toa solution of 110 mg (0.17 mmol) of the thus-obtained amorphous powderin ethanol (10 ml) was 0.35 ml (0.35 mmol) of 1N hydrochloric acid, andthe resultant mixture was concentrated under reduced pressure, therebyobtaining the title compound as a pale yellow amorphous powder.

¹H-NMR (DMSO-d₆, 120° C.) (no N⁺H proton of the ammonium salt wasobserved) δ: 2.81(br s,6H), 2.87-3.50(m,5H), 3.72(s,6H), 3.82(s,12H),3.99-4.38(m,3H), 5.01(m,1H), 6.74(br d,J=14.7 Hz,2H), 6.83(s,2H),6.84(s,2H), 6.89(br d,J=15.5 Hz,2H), 7.03(dd,J=15.5,10.5 Hz,1H),7.04(dd,J=15.5,10.5 Hz,1H), 7.29(dd,J=14.7,10.5 Hz,1H),7.30(dd,J=14.7,10.5 Hz,1H).

Example 37

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-(N,N-diisopropylaminomethyl)piperazinefumarate:

In accordance with the same process as in Example 33, 108 mg (yield:57%) of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-(N,N-diisopropylaminomethyl)piperazinewas obtained as a pale yellow amorphous powder from 153 mg (0.58 mmol)of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 85 mg (0.27mmol) of 2-(N,N-di-isopropylaminomethyl)piperazine trihydrochloridesynthesized by the same process as in Referential Example 2. Added to asolution of 88 mg (0.12 mmol) of the thus-obtained amorphous powder inethanol (10 ml) was 15 mg (0.12 mmol) of fumaric acid, and the resultantmixture was concentrated under reduced pressure, thereby obtaining thetitle compound as a pale yellow amorphous powder.

¹H-NMR (data for free base of the title compound) (DMSO-d₆, 120° C.) δ:0.95(d,J=6.6 Hz,6H), 0.98(d,J=6.6 Hz,6H), 2.51-2.56(m,2H),3.03(qq,J=6.6,6.6 Hz,2H), 2.95-3.30(m,3H), 3.72(s,6H), 3.82(s,12H),4.02-4.45(m,4H), 6.65(br d,J=14.7 Hz,2H), 6.81(s,2H), 6.82(s,2H),6.84(d,J=15.5 Hz,1H), 6.85(d,J=15.5 Hz,1H), 6.96(dd,J=15.5,10.4 Hz,1H),7.00(dd,J=15.5,10.4 Hz,1H), 7.24(dd,J=14.7,10.4 Hz,1H),7.26(dd,J=14.7,10.4 Hz,1H).

Example 38

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-morpholinomethylpiperazinefumarate:

In accordance with the same process as in Example 33, 234 mg (yield:62%) of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-morpholinomethylpiperazinewas obtained as pale yellow amorphous powder from 325 mg (1.2 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 165 mg (0.55mmol) of 2-morpholinomethylpiperazine trihydrochloride synthesized bythe same process as in Referential Example 2. Added to a solution of 204mg (0.30 mmol) of the thus-obtained amorphous powder in ethanol (10 ml)was 35 mg (0.30 mmol) of fumaric acid, and the resultant mixture wasconcentrated under reduced pressure, thereby obtaining the titlecompound as a pale yellow amorphous powder.

¹H-NMR (DMSO-d₆, 120° C.) (neither N⁺H proton of the ammonium salt norOH proton of the carboxyl group was observed) δ: 2.30-2.50(m,6H),2.95-3.25(m,3H), 3.56-3.66(m,4H), 3.79(s,6H), 3.88(s,12H),4.08-4.65(m,4H), 6.68(br d,J=14.4 Hz,2H), 6.69(s,2H), 6.87(s,4H),6.90(d,J=15.5 Hz,1H), 6.90(d,J=15.5 Hz,1H), 7.02(dd,J=15.5,10.2 Hz,2H),7.30(dd,J=14.4,10.2 Hz,1H), 7.32(dd,J=14.4,10.2 Hz,1H)

Example 39

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-(imidazol-1-ylmethyl)piperazinefumarate:

In accordance with the same process as in Example 33, 74 mg (yield: 30%)of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-(imidazol-1-ylmethyl)piperazinewas obtained as a pale yellow amorphous powder from 221 mg (0.83 mmol)of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 105 mg (0.38mmol) of 2-(imidazol-1-ylmethyl)piperazine trihydrochloride synthesizedby the same process as in Referential Example 2. Added to a solution of74 mg (0.11 mmol) of the thus-obtained amorphous powder in ethanol (10ml) was 13 mg (0.11 mmol) of fumaric acid, and the resultant mixture wasconcentrated under reduced pressure, thereby obtaining the titlecompound as a pale yellow amorphous powder.

¹H-NMR (DMSO-d₆, 120° C.) (neither N⁺H proton of the ammonium salt norOH proton of the carboxyl group was observed) δ: 3.02-3.57(m,5H),3.74(s,6H), 3.82(s,12H), 4.05-4.28(m,3H), 4.64-4.78(m,1H),6.33-6.48(m,2H), 6.60-6.94(m,5H), 6.62(s,2H), 6.80(s,2H), 6.82(s,2H),7.08(t,J=1.0 Hz,1H), 7.11-7.33(m,2H), 7.47-7.53(m,1H).

Example 40

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-phenylthiomethylpiperazine:

In accordance with the same process as in Example 33, 270 mg (yield:56%) of the title compound was obtained as a pale yellow amorphouspowder from 489 mg (1.7 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 203 mg (0.69mmol) of 2-phenylthiomethylpiperazine dihydrochloride synthesized by thesame process as in Referential Example 2.

¹H-NMR (CDCl₃) δ: 2.97-3.33(m,3H), 3.16(d,J=7.6 Hz,2H), 3.73(s,3H),3.73(s,3H), 3.83(s,6H), 3.84(s,6H), 4.07-4.21(m,2H), 4.29-4.44(m,1H),4.44-4.58(m,1H), 6.43(d,J=14.7 Hz,1H), 6.63(d,J=14.7 Hz,1H),6.74-6.92(m,3H), 6.80(s,2H), 6.82(s,2H), 6.97(dd,J=15.5,10.1 Hz,1H),7.16-7.35(m,5H), 7.39-7.46(m,2H).

Example 41

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-1,2,3,4-tetrahydroquinoxaline:

A solution of 185 mg (0.70 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid in anhydrousdimethylformamide-methylene chloride (0.2 ml-2 ml) was cooled in an icebath. To the solution was added 0.10 ml (1.1 mmol) of oxalyl chloridewith stirring. The ice bath was removed, and the mixture was stirred for30 minutes at room temperature. The reaction mixture was concentratedunder reduced pressure to obtain crude crystals of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl chloride.

A solution of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl chloridein methylene chloride (3 ml) was added dropwise to a solution of 45 mg(0.34 mmol) of 1,2,3,4-tetrahydroquinoxaline⁽¹⁾ in pyridine (0.5 ml)over about 5 minutes with stirring in an ice bath. After completion ofthe addition, the mixture was stirred for 1 hour and water was added toconduct extraction with chloroform. An organic layer was dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The resultant crude oil (254 mg) was purified by column chromatographyon alumina and column chromatography on silica gel to obtain 91 mg(yield: 43%) of crude crystals of the title compound. The crude crystalswere recrystallized from chloroform-ether to obtain pale yellow fienneedles.

(1) Bugle, R. C.; Osteryoung, R. A., J. Org. Chem., 1979, 44, 1719-1720.

Melting point: 183-185° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 3.71(s,6H), 3.80(s,12H), 3.97(s,4H),6.52(d,J=14.9 Hz,2H), 6.80(s,4H), 6.85-7.00(m,4H), 7.21-7.28(m,2H),7.36(ddd,J=14.9,9.0,1.1 Hz,2H), 7.38-7.45(m,2H).

Example 42

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-pyrido[2,3-b]-1,2,3,4-tetrahydropyrazine:

In accordance with the same process as in Example 41, 190 mg (yield:40%) of crude crystals of the title compound were obtained from 477 mg(1.8 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and102 mg (0.75 mmol) of pyrido[2,3-b]-1,2,3,4-tetrahydropyrazine⁽¹⁾. Thecrude crystals were recrystallized from ethanol to obtain pale yellowfine needles.

(1) Bugle, R. C.; Osteryoung, R. A., J. Org. Chem, 1979, 44, 1719-1720.

Melting point: 183-185° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 3.72(s,3H), 3.73(s,3H), 3.81(s,6H),3.81(s,6H), 4.00(s,4H), 6.58(d,J=14.7 Hz,1H), 6.83(s,2H), 6.83(s,2H),6.88-7.05(m,5H), 7.21(dd,J=8.1,4.8 Hz,1H), 7.35(ddd,J=14.7,8.9,1.1Hz,1H), 7.39(ddd,J=14.7,8.9,1.1 Hz,1H), 8.02(dd,J=8.1,1.7 Hz,1H),8.19(dd,J=4.8,1.7 Hz,1H).

Referential Example 3

Preparation of6-(N,N-dimethylamino)hexahydro-1,4-diazepine.trihydrobromide:

To a solution of 0.53 ml (6.1 mmol) of oxalyl chloride in anhydroustetrahydrofuran (15 ml) at −78° C. under nitrogen was added dropwise asolution of 0.50 ml (7.0 mmol) of anhydrous dimethyl sulfoxide inanhydrous tetrahydrofuran (2 ml). After 10 minutes, a solution of 2.0 g(4.7 mmol) of1,4-bis(p-toluenesulfonyl)-6-hydroxy-hexahydro-1,4-diazepine⁽¹⁾ inanhydrous dimethyl sulfoxide-tetrahydrofuran (2 ml-5 ml) was addeddropwise. After 20 minutes at −78° C., 1.3 ml (9.3 mmol) oftriethylamine was added dropwise. The cooling bath was removed, and themixture was stirred for 45 minutes at room temperature. Water (3 ml) anda saturated saline solution (3 ml) were added to the reaction mixture toconduct extraction with ether. An organic layer was dried over anhydroussodium sulfate and then concentrated under reduced pressure, and theresultant crude oil was purified by chromatography on silica gel,thereby obtaining 1.0 g (yield: 52%) of1,4-bis(p-toluenesulfonyl)-6-oxohexahydro-1,4-diazepine as a colorlessoil.

(1) Saari. W. S.; Raab, A. W.; King, S. W., J. Org. Chem., 1971, 36,1711-1714.

Addition of 102 mg (1.8 mmol) of potassium hydroxide to a solution of479 mg (5.9 mmol) of dimethylamine hydrochloride in methanol (4 ml) gavea clear solution. To this solution were added 979 mg (2.3 mmol) of1,4-bis(p-toluenesulfonyl)-6-oxohexahydro-1,4-diazepine synthesized bythe above process in methanol (30 ml) and 116 mg (1.8 mmol) of sodiumcyanoborohydride. After the resultant mixture was stirred for 15 hoursat room temperature, 104 mg (1.7 mmol) of additional sodiumcyanoborohydride was added, and the mixture was stirred for anadditional 25 hours. A 1N aqueous solution (5 ml) of sodium hydroxidewas added to the reaction mixture, and the mixture was concentratedunder reduced pressure, followed by extraction with chloroform. Anorganic layer was dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel to obtain 519 mg (yield:50%) of1,4-bis(p-toluenesulfonyl)-6-(N,N-dimethylamino)-hexahydro-1,4-diazepineas a colorless oil.

Weighed out to a reaction vessel was 250 mg (0.56 mmol) of1,4-bis(p-toluenesulfonyl)-6-(N,N-dimethylamino)-hexahydro-1,4-diazepinesynthesized by the above process, and 0.20 ml (2.3 mmol) of phenol and a30% acetic acid solution (4 ml) of hydrobromic acid were added, followedby stirring for 6 hours in a bath controlled to 70° C. After thereaction mixture was concentrated under reduced pressure, diethyl ether(5 ml) was added to the residue with stirring, and a supernatant wasremoved. This process was repeated twice to remove diethyl ether-solublematerial. The residue was concentrated again under reduced pressure tocompletely remove diethyl ether. Ethanol (2 ml) was added to theresultant residue, and the mixture was stirred for 30 minutes. Diethylether (2 ml) was added to the resultant solution, and the mixture wascooled in an ice bath, thereby obtaining 194 mg (yield: 91%) of thetitle compound as a colorless crystalline powder (melting point: 245°C., decomposed).

Example 43

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-6-(N,N-dimethylamino)hexahydro-1,4-diazepinehydrochloride:

In accordance with the same process as in Example 33, 255 mg(quantitative) of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-6-(N,N-dimethylamino)-hexahydro-1,4-diazepinewere obtained as a colorless amorphous powder from 254 mg (0.96 mmol) of5-(3.4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 155 mg (0.40mmol) of 6-(N,N-dimethylamino)hexahydro-1.4-diazepine trihydrobromidesynthesized by the process described in Referential Example 3. Added toa solution of 104 mg (0.16 mmol) of the resultant amorphous powder inethanol (4 ml) was 0.30 ml (0.30 mmol) of 1N hydrochloric acid, and themixture was concentrated under reduced pressure, thereby obtaining thetitle compound as a yellow amorphous powder.

¹H-NMR (DMSO-d₆, 120° C.) δ: 2.85(s,6H), 3.38-3.63(m,5H), 3.72(s,6H),3.80(s,12H), 3.90-4.09(m,2H), 4.12-4.24(m,2H), 6.70(d,J=14.7 Hz,2H),6.80(s,4H), 6.86(d,J=15.6 Hz,2H), 6.99(dd,J=15.6,10.4 Hz,2H),7.26(dd,J=14.7,10.4 Hz,2H).

Example 44

Preparation of1.4-bis[5-(2.3,4-trimethoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 41, 269 mg (yield:86%) of crude crystals of the title compound were obtained from 308 mg(1.2 mmol) of 5-(2,3,4-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and53 mg (0.53 mmol) of homopiperazine. The crude crystals wererecrystallized from ethyl acetate-hexane, thereby obtaining a paleyellow crystalline powder.

Melting point: 172-175° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.83(tt,J=5.9,5.9 Hz,2H), 3.57(dd,J=5.9,5.9Hz,4H), 3.75-3.85(m,4H), 3.78(s,6H), 3.80(s,6H), 3.82(s,6H),6.55(d,J=15.3 Hz,2H), 6.77(d,J=8.8 Hz,2H), 6.86-7.12(m,4H),7.15-7.28(m,2H), 7.22(d,J=8.8 Hz,2H).

Example 45

Preparation of1,4-bis[5-(3,4,5-trimethylphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 41, 140 mg (yield:56%) of the title compound was obtained as pale yellow amorphous powderfrom 238 mg (1.1 mmol) of 5-(3,4,5-trimethylphenyl)penta-(2E,4E)-dienoicacid and 50 mg (0.50 mmol) of homopiperazine.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.80(tt,J=5.8,5.8 Hz,2H), 2.12(s,6H),2.22(s,12H), 3.56(dd,J=5.8,5.8 Hz,4H), 3.67(s,4H), 6.56(d,J=14.6 Hz,2H),6.77(d,J=15.6 Hz,2H), 6.93(dd,J=15.6,10.5HZ,2H), 7.09(s,4H),7.20(dd,J=14.6,10.5 Hz,2H).

Example 46

Preparation of1,4-bis[5-(4-tert-butyl-2-methoxyphenyl)penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)piperazinehydrochloride:

In accordance with the same process as in Example 41, 85 mg (yield: 68%)of1,4-bis[5-(4-tert-butyl-2-methoxyphenyl)penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)piperazinewas obtained as a pale yellow amorphous powder from 114 mg (0.44 mmol)of 5-(4-tert-butyl-2-methoxyphenyl)penta-(2E,4E)-dienoic acid and 50 mg(0.20 mmol) of 2-(N,N-dimethylaminomethyl)piperazine trihydrochloridesynthesized by the process described in Referential Example 2.

Added to a solution of 85 mg (0.14 mmol) of the thus-obtained amorphouspowder in ethanol (10 ml) was 0.30 ml (0.3 mmol) of 1N hydrochloricacid, and the resultant mixture was concentrated under reduced pressure,thereby obtaining the title compound as a pale yellow amorphous powder.

¹H-NMR (data for free base of the title compound) (DMSO-d₆, 120° C.) δ:1.30(s,18H), 2.22(s,6H), 2.95-3.20(m,5H), 3.85(s,6H), 4.00-4.50(m,4H),6.59(dd,J=14.5,4.2 Hz,2H), 6.85-7.15(m,8H), 7.26(dd,J=14.8,9.7 Hz,2H),7.43(d,J=7.5 Hz,2H).

Example 47

Preparation of1,4-bis[5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)piperazinehydrochloride:

In accordance with the same process as in Example 41, 83 mg (yield: 53%)of1,4-bis[5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)piperazinewas obtained as a pale yellow amorphous powder from 144 mg (0.62 mmol)of 5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 71 mg (0.28mmol) of 2-(N,N-dimethylaminomethyl)piperazine trihydrochloridesynthesized by the process described in Referential Example 2.

Added to a solution of 83 mg (0.14 mmol) of the thus-obtained amorphouspowder in ethanol (10 ml) was 0.30 ml (0.3 mmol) of 1N hydrochloricacid, and the resultant mixture was concentrated under reduced pressure,thereby obtaining the title compound as a pale yellow amorphous powder.

¹H-NMR (data for free base of the title compound) (DMSO-d₆, 120° C.) δ:2.23(s,6H), 2.90-3.25(m,5H), 3.84(s,12H), 4.00-4.50(m,4H),6.54(dd,J=14.0,3.9 Hz,2H), 6.67(d,J=8.5 Hz,4H), 7.15-7.35(m,8H).

Example 48

Preparation ofN-[1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-piperazinylmethyl]-phthalimide(in the formula, NPhth is a phthalimide group):

In accordance with the same process as in Example 41, 533 mg (yield:75%) of the title compound was obtained as a pale yellow amorphouspowder from 581 mg (2.2 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 334 mg (1.0mmol) of N-(2-piperazinylmethyl)phthalimide dihydrochloride synthesizedby the same process as in Referential Example 2.

¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:2.91-3.55(m,5H), 3.61-3.75(m,6H), 3.75-3.91(m,12H), 3.99-4.38(m,3H),4.72-4.88(m,1H), 6.35-6.51(m,2H), 6.52-7.02(m,9H), 7.29(dd,J=14.4,10.1Hz,1H), 7.68-7.82(m,4H).

Example 49

Preparation of2-aminomethyl-1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazinehydrochloride:

A solution of 1.3 ml (26 mmol) of hydrazine hydrate in methanol (2 ml)was added to a suspension of 430 mg (0.58 mmol) ofN-[1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-piperazinylmethyl]phthalimidesynthesized by the process described in Example 48 in methanol (8 ml),and the mixture was stirred for 17 hours at room temperature. Thereaction mixture was concentrated under reduced pressure, and theresultant residue was extracted with chloroform. An organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate andwater, dried over anhydrous sodium sulfate, and then concentrated underreduced pressure. The resultant crude oil was purified by columnchromatography on silica gel to obtain 232 mg (yield: 65%) of2-aminomethyl-1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazineas a pale yellow amorphous powder.

Added to a solution of 93 mg (0.15 mmol) of the thus-obtained amorphouspowder in ethanol (10 ml) was 0.30 ml (0.3 mmol) of 1N hydrochloricacid, and the resultant mixture was concentrated under reduced pressure,thereby obtaining the title compound as a pale yellow amorphous powder.

¹H-NMR (DMSO-d₆, 120° C.) δ: (No N⁺H proton of the ammonium salt wasobserved) 3.03(br d,J=6.8 Hz,2H), 3.16-3.39(m,3H), 3.72(s,6H),3.73(s,12H), 4.01-4.32(m,3H), 4.68-4.81(m,1H), 6.70(d,J=14.6 Hz,2H),6.82(s,4H), 6.86(d,J=14.6 Hz,2H), 6.97(dd,J=14.6,10.2 Hz,2H),7.28(dd,J=14.6,10.2 Hz,2H).

Referential Example 4

Preparation of2,5-bis-tert-butoxycarbonyl-8-methyl-2,5,8-triazabicyclo[4,3,0]nonane:

Added to a solution of 792 mg (12 mmol) of potassium hydroxide in water(38.5 ml) were 1.00 g (6.0 mmol) of pyrazine-2,3-dicarboxylic acid and300 mg of 10% palladium on carbon, and the mixture was stirred for 16hours at 50° C. under hydrogen. The catalyst was removed from thereaction mixture by suction filtration through Celite. A concentratedhydrochloric acid was added until the pH of the filtrate was 3, and thesolution was concentrated under reduced pressure. Added to a solution ofthe resultant residue in methanol (20 ml) were 2.5 ml (18 mmol) oftriethylamine and 4.0 g (18 mmol) of di-tert-butyl dicarbonate. Afterthe resultant mixture was stirred for 30 minutes at room temperature,the reaction mixture was concentrated under reduced pressure. Chloroformwas added to the resultant residue, and the resultant solution waswashed successively with water, 2N hydrochloric acid, and a saturatedsaline solution. An organic layer was dried over anhydrous sodiumsulfate and then concentrated under reduced pressure, thereby obtaining2.5 g of an oil containing1,4-bis(tert-butoxycarbonyl)-piperazine-2,3-dicarboxylic acid.

Added to a solution of 2.5 g of the oil in xylene (20 ml) was 0.65 ml(5.9 mmol) of benzylamine, and the mixture was stirred and refluxed for1 hour with continuous removal of water by a water separator. Thereaction mixture was concentrated under reduced pressure, and theresultant residue was purified by column chromatography on silica gel,thereby obtaining 650 mg (yield: 25%) of8-benzyl-2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo[4,3,0]nonane-7,9-dioneas a colorless oil.

To a solution of 650 mg (1.5 mmol) of8-benzyl-2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo-[4,3,0]nonane-7,9-dionein tetrahydrofuran (10 ml) was added 4N hydrogen chloride solution inethyl acetate (10 ml) with stirring. After 30 minutes at 50° C., a 2.5Naqueous solution of sodium hydroxide (17 ml) was added to the reactionmixture, and the mixture was extracted with chloroform. An organic layerwas dried over anhydrous sodium sulfate and then concentrated underreduced pressure. The resultant crude oil was purified by columnchromatography on silica gel, thereby obtaining 85 mg (yield: 24%) of8-benzyl-2,5,8-triazabicyclo[4,3,0]nonane-7,9-dione as a colorless oil.

To a solution of 80 mg (0.33 mmol) of8-benzyl-2,5,8-triazabicyclo[4,3,0]nonane-7,9-dione in diethylene glycoldimethyl ether (1 ml) were added 38 mg (1.0 mmol) of sodium borohydrideand 0.20 ml (1.6 mmol) of a boron trifluoridediethyl ether complex withstirring for 2 hours at 70° C. under nitrogen. 6N Hydrochloric acid(0.53 ml) was added, and the mixture was stirred for 15 minutes a thesame temperature. To the reaction mixture was added 242 mg (5.8 mmol) ofsodium fluoride with stirring. After 30 minutes at 100° C., a 5N aqueoussolution of sodium hydroxide (0.5 ml) was added, and the mixture wasconcentrated under reduced pressure. The resultant residue was extractedwith diethyl ether, and an organic layer was dried over anhydrous sodiumsulfate and then concentrated under reduced pressure, thereby obtaining19 mg of a crude oil containing8-benzyl-2,5,8-triazabicyclo-[4,3,0]nonane.

Added to a solution of 19 mg of this oil in tetrahydrofuran (1 ml) were0.030 ml (0.22 mmol) of triethylamine and 44 mg (0.20 mmol) ofdi-tert-butyl dicarbonate. After the resultant mixture was stirred for30 minutes at room temperature, the reaction mixture was concentratedunder reduced pressure. The resultant residue was purified bypreparative thin-layer chromatography on silica gel, thereby obtaining39 mg (yield: 25%) of8-benzyl-2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo-[4,3,0]nonaneas a colorless oil.

To a solution of 39 mg (0.093 mmol) of8-benzyl-2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo-[4,3,0]nonanesynthesized by the above process in methanol (1.5 ml) were added 40 mg(0.63 mmol) of ammonium formate and 40 mg of 10% palladium on carbon.The mixture was stirred for 1 hour at 70° C. under nitrogen, and thecatalyst was removed from the reaction mixture by suction filtrationthrough Celite. The filtrate was concentrated under reduced pressure,and the resultant crude oil was purified by column chromatography onsilica gel, thereby obtaining 29 mg (yield: 95%) of2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo[4,3,0]nonane as acolorless oil.

Added to a solution of 29 mg of the thus obtained2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo[4,3,0]-nonane inacetonitrile (0.7 ml) were 0.038 ml (0.51 mmol) of a 37% aqueoussolution of formaldehyde and 9.4 mg (0.15 mmol) of sodiumcyanoborohydride. After the mixture was stirred for 1 hour and 20minutes at room temperature, acetic acid was added until the reactionmixture reached pH 4, and the resultant mixture was stirred for 30minutes at room temperature. The reaction mixture was concentrated underreduced pressure, and the resultant crude oil was purified by columnchromatography on silica gel, thereby obtaining 29 mg (yield: 96%) ofthe title compound as a colorless oil.

Example 50

Preparation of2,5-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-8-methyl-2,5,8-triazabicyclo[4,3,0]-nonanehydrochloride:

To a solution of 29 mg (0.085 mmol) of2,5-bis-tert-butoxycarbonyl-8-methyl-2,5,8-triazabicyclo[4,3,0]nonanesynthesized by the process described in Referential Example 4 intetrahydrofuran (1 ml) was added 4N hydrogen chloride solution in ethylacetate (1 ml) with stirring. After 30 minutes at room temperature, andanother 30 minutes at 50° C., the reaction mixture was concentratedunder reduced pressure, thereby obtaining 21 mg of an oil containing8-methyl-2,5,8-triaza-bicyclo[4,3,0]nonane.

In accordance with the same process as in Example 41, 30 mg (yield: 56%)of2,5-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-8-methyl-2,5,8-triazabicyclo[4,3,0]-nonanewere obtained as a pale yellow amorphous powder from 21 mg of this oiland 58 mg (0.22 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoicacid.

Added to a solution of 30 mg (0.047 mmol) of the thus-obtained amorphouspowder in ethanol (10 ml) was 0.10 ml (0.10 mmol) of 1N hydrochloricacid, and the resultant mixture was concentrated under reduced pressure,thereby obtaining the title compound as a pale yellow amorphous powder.

¹H-NMR (data for free base of the title compound) (DMSO-d₆, 120° C.) δ:2.28(s,3H), 2.55-2.64(m,2H), 3.20-3.30(m,2H), 3.50-3.67(m,4H),3.72(s,6H), 3.82(s,12H), 4.80-4.88(m,2H), 6.61(d,J=14.7 Hz,2H),6.81(s,4H), 6.84(d,J=15.5 Hz,2H), 6.97(dd,J=15.5,10.4 Hz,2H),7.27(dd,J=14.7,10.4 Hz,2H).

Example 51

Preparation of4,8-bis[5-(3,4-dimethoxyphenyl)penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanehydrochloride:

In accordance with the same process as in Example 41, 117 mg (yield:72%) of4,8-bis[5-(3,4-dimethoxyphenyl)penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanewas obtained as a pale yellow amorphous powder from 146 mg (0.62 mmol)of 5-(3,4-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 40 mg (0.28mmol) of 1,4,8-triazabicyclo[4,4,0]-decane⁽¹⁾.

(1) Gubert, S; Braojos, C; Sacristan, A; Ortiz, J. A., Synthesis, 1991,318-320.

Added to a solution of 117 mg (0.20 mmol) of the thus-obtained amorphouspowder in ethanol (10 ml) was 0.40 ml (0.40 mmol) of 1N hydrochloricacid, and the resultant mixture was concentrated under reduced pressureto obtain crude crystals of the title compound. The crude crystals wererecrystallized from methanol-diethyl ether, thereby obtaining a paleyellow crystalline powder.

Melting point: 220° C. (decomposed).

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.92(br dd,J=10.5,10.5 Hz,1H),2.10(ddd,J=12.0,12.0,3.0 Hz,2H), 2.60-2.70(m,2H), 2.75-2.90(m,2H),2.95-3.10(m,2H), 3.79(s,6H), 3.81(s,6H), 4.21(br d,J=10.5 Hz,4H),6.62(d,J=14.7 Hz,2H), 6.83(br d,J=14.4 Hz,2H), 6.91(dd,J=14.4,8.7Hz,2H), 6.93(d,J=8.3 Hz,2H), 7.04(dd,J=8.3,2.0 Hz,2H), 7.11(d,J=2.0Hz,2H), 7.22(ddd,J=14.7,8.7,1.3 Hz,2H).

Example 52

Preparation of4,8-bis[5-(3,4,5-trimethylphenyl)penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanehydrochloride:

In accordance with the same process as in Example 41, 83 mg (yield: 66%)of4,8-bis[5-(3,4,5-trimethylphenyl)penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanewas obtained as a pale yellow amorphous powder from 111 mg (0.52 mmol)of 5-(3,4,5-trimethylphenyl)penta-(2E,4E)-dienoic acid and 33 mg (0.23mmol) of 1,4,8-triazabicyclo[4,4,0]-decane⁽¹⁾.

(1) Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A., Synthesis,1991, 318-320.

Added to a solution of 83 mg (0.15 mmol) of the thus-obtained amorphouspowder in ethanol (10 ml) was 0.30 ml (0.30 mmol) of 1N hydrochloricacid, and the resultant mixture was concentrated under reduced pressureto obtain crude crystals of the title compound. The crude crystals wererecrystallized from methanol-diethyl ether, thereby obtaining a paleyellow crystalline powder.

Melting point: 250° C. (decomposed).

¹H-NMR (DMSO-d₆, 120° C.) δ: 2.18(s,6H), 2.00-2.25(m,5H), 2.29(s,12H),2.80-2.95(m,4H), 3.90-4.10(m,2H), 4.60-4.70(m,2H), 6.40(d,J=14.6 Hz,2H),6.75-6.90(m,4H), 7.26(s,4H), 7.45(dd,J=15.8,10.6 Hz,2H).

Referential Example 5

Preparation of 3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)prop-(2E)-ene:

In accordance with the same process as in Referential Example 1, 1.25 g(65%) of crude crystals of the title compound were obtained from 1.60 g(7.4 mmol) of 3,4-dihydro-6,7-dimethoxy-2-naphthalenecarbaldehyde⁽¹⁾ and2.20 g (9.7 mmol) of triethyl phosphonoacetate. The crude crystals wasrecrystallized from ethyl acetate, thereby obtaining pale yellow flakes.

(1) Narasimham, N. S.; Mukhopadhyay, T.; Kusurkar, S. S., Indian J.Chem., 1981, 20B, 546-548.

Melting point: 225-227° C.

Example 53

Preparation of1,4-bis[3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 41, 290 mg (yield:97%) of crude crystals of the title compound were obtained from 292 mg(1.1 mmol) of 3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)prop-(2E)-enoicacid and 51 mg (0.51 mmol) of homopiperazine. The crude crystals wererecrystallized from chloroform-hexane, thereby obtaining pale yellowcrystalline powder.

Melting point: 255° C. (decomposed).

¹H-NMR (CDCl₃) (mixture of amide rotamers) δ: 2.10-2.95(m,2H),2.43-2.57(m,4H), 2.86(br dd,J=8.0,8.0 Hz,4H), 3.60-4.00(m,8H),3.88(s,6H), 3.90(s,6H), 6.28-6.41(m,2H), 6.65-6.74(m,6H),7.47-7.63(m,2H).

Referential Example 6

Preparation of3-(3,4-dihydro-6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoic acid:

In accordance with the same process as in Referential Example 1, 308 mg(yield: 72%) of crude crystals of the title compound were obtained from367 mg (1.5 mmol) of3,4-dihydro-6,7,8-trimethoxy-2-naphthalenecarbaldehyde⁽¹⁾ and 404 mg(1.8 mmol) of triethyl phosphonoacetate. The crude crystals wererecrystallized from ethyl acetate-hexane, thereby obtaining a paleyellow crystalline powder.

(1) Narasimham, N. S.; Mukhopadhyay, T.; Kusurkar, S. S., Indian J.Chem., 1981, 20B, 546-548.

Melting point: 191-194° C.

Example 54

Preparation of1,4-bis[3-(3,4-dihydro-6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoyl]piperazine:

In accordance with the same process as in Example 41, 365 mg(quantitative) of crude crystals of the title compound were obtainedfrom 370 mg (1.3 mmol) of3-(3,4-dihydro-6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoic acidsynthesized by the process described in Referential Example 6 and 50 mg(0.58 mmol) of piperazine. The crude crystals were recrystallized fromchloroform-hexane, thereby obtaining a pale yellow crystalline powder.

Melting point: 241-244° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 2.48(dd,J=8.0,8.0 Hz,4H), 2.83(dd,J=8.0,8.0Hz,4H), 3.60-3.80(m,8H), 3.86(s,6H), 3.89(s,6H), 3.91(s,6H),6.35(d,J=15.1 Hz,2H), 6.52(s,2H), 7.04(s,2H), 7.57(d,J=15.1 Hz,2H).

Referential Example 7

Preparation of3-(3,4-dihydro-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoic acid:

To 612 mg (8.4 mmol) of dimethylformamide was added 0.20 ml (2.1 mmol)of phosphorus oxychloride with stirring in an ice bath. The ice bath wasremoved and the reaction mixture was stirred at room temperature. After5 minutes, 460 mg (2.1 mmol) of3,4-dihydro-5,6,7-trimethoxy-naphthalene⁽¹⁾ was added to the resultantsolution, and the resultant mixture was stirred for 10 minutes at 50° C.and for 3 hours at 80° C. A 2N aqueous solution of potassium acetate (6ml) chilled with ice was added to the reaction mixture to conductextraction with diethyl ether. An organic layer was washed with asaturated aqueous solution of sodium hydrogen-carbonate and a saturatedsaline solution, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The resultant crude oil (520 mg)was purified by column chromatography on silica gel, thereby obtaining291 mg (yield: 56%) of3,4-dihydro-5,6,7-trimethoxy-2-naphthalenecarbaldehyde as a colorlessoil.

(1) Haworth, R. D.; Moore, B. P.; Pauson, P. L., J. Chem. Soc., 1949,3271-3278.

In accordance with the same process as in Referential Example 1, 173 mg(yield: 99%) of crude crystals of the title compound were obtained from150 mg (0.60 mmol) of3,4-dihydro-5,6,7-trimethoxy-2-naphthalenecarbaldehyde synthesized bythe above process and 176 mg (0.79 mmol) of triethyl phosphonoacetate.The crude crystals were recrystallized from ethyl acetate-hexane,thereby obtaining a pale yellow crystalline powder.

Melting point: 191-193° C.

Example 55

Preparation of1,4-bis[3-(3,4-dihydro-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 41, 98 mg (yield: 76%)of crude crystals of the title compound were obtained from 131 mg (0.45mmol) of 3-(3,4-dihydro-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoic acidsynthesized by the process described in Referential Example 7 and 20 mg(0.20 mmol) of homopiperazine. The crude crystals were recrystallizedfrom chloroform-hexane, thereby obtaining a pale yellow crystallinepowder.

Melting point: 176-179° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.80(tt,J=6.0,6.0 Hz,2H), 2.43(dd,J=8.1,8.1Hz,4H), 2.74(dd,J=8.1,8.1 Hz,4H), 3.59(dd,J=6.0,6.0 Hz,4H), 3.71(s,4H),3.75(s,6H), 3.77(s,6H), 3.78(s,6H), 6.50(d,J=15.1 Hz,2H), 6.62(s,2H),6.67(s,2H), 7.22(d,J=15.1 Hz,2H).

Referential Example 8

Preparation of3-(3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoicacid:

To anhydrous tetrahydrofuran (10 ml) stirred in an ice bath undernitrogen were added 104 mg (15 mmol) of lithium, 3.9 g (14 mmol) of1-bromo-3-(3,4,5-trimethoxyphenyl)propane ⁽¹⁾, and a solution of 0.95 ml(13 mmol) of acetone in tetrahydrofuran (10 ml). After the mixture wasstirred for 17 hours at room temperature, a 2% aqueous solution ofacetic acid (50 ml) chilled with ice was added to conduct extractionwith diethyl ether. An organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and a saturated saline solution,dried over anhydrous sodium sulfate and then concentrated under reducedpressure. The resultant crude oil (4.1 g) was purified by columnchromatography on silica gel, thereby obtaining 860 mg (yield: 24%) of2-methyl-5-(3,4,5-trimethoxyphenyl)pentan-2-ol.

(1) Evans, D. A.; Tannis, S. P.; Hart. D. J., J. Am. Chem. Soc., 1981,103, 5813-5821.

To 908 mg (3.4 mmol) of 2-methyl-5-(3,4,5-trimethoxyphenyl)pentan-2-olcooled in an ice bath was added 5 mg (80 mmol) of 85% sulfuric acidchilled with ice, and the mixture was stirred for 30 minutes. Ice waterwas added to the reaction mixture to conduct extraction with diethylether. An organic layer was washed with a saturated aqueous solution ofsodium hydrogencarbonate and a saturated saline solution, dried overanhydrous sodium sulfate and then concentrated under reduced pressure,thereby obtaining 848 mg of a crude oil containing1,1-dimethyl-1,2,3,4-tetrahydro-6,7,8-trimethoxynaphthalene.

Added to a solution of 848 mg (about 3.4 mmol) of this oil in carbontetrachloride (45 ml) were 713 mg (4.0 mmol) of N-bromosuccinimide and23 mg (0.095 mmol) of benzoyl peroxide, and the mixture was stirred for3 hours at 85° C. The reaction mixture was washed with a saturatedaqueous solution of sodium hydrogencarbonate and a saturated salinesolution, dried over anhydrous sodium sulfate and then concentratedunder reduced pressure. The resultant crude oil was purified by columnchromatography on silica gel, thereby obtaining 430 mg (yield: 51%) of3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-naphthalene.

In accordance with the same process as in Referential Example 7, 81 mg(yield: 25%) of3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-2-naphthalenecarbaldehyde wassynthesized from 294 mg (1.2 mmol) of3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxynaphthalene synthesized by theabove process, and 95 mg (yield: 84%) of crude crystals of the titlecompound were then obtained from 98 mg (0.36 mmol) of3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-2-naphthalenecarbaldehyde. Thecrude crystals were recrystallized from diethyl ether-hexane, therebyobtaining pale yellow needles.

Melting point: 178-180° C.

Example 56

Preparation of1,4-bis[3-(3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 41, 55 mg (yield: 58%)of crude crystals of the title compound were obtained from 95 mg (0.29mmol) of3-(3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoicacid synthesized by the process described in Referential Example 8 and14 mg (0.14 mmol) of homopiperazine. The crude crystals wererecrystallized from ethyl acetate-hexane, thereby obtaining a paleyellow crystalline powder.

Melting point: 205-207° C.

¹H-NMR (DMSO-d₆, 120° C.) δ:

1.31(s,12H), 1.85(tt,J=6.0,6.0 Hz,2H), 2.31(s,4H), 3.60(dd,J=6.0,6.0Hz,4H), 3.71(s,4H), 3.77(s,12H), 3.79(s,6H), 6.50(d,J=15.1 Hz,2H),6.62(s,2H), 6.63(s,2H), 7.23(d,J=15.1 Hz,2H).

Referential Example 9

Preparation of 3-(6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoic acid:

Added to a solution of 100 mg (0.34 mmol) of3-(3,4-dihydro-6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoic acidsynthesized by the process described in Referential Example 6 in toluene(2 ml) was 102 mg (0.41 mmol) of2,3-dichloro-5,6-dicyano-p-benzoquinone, and the mixture was stirred for1 hour and 30 minutes at 100° C. The reaction mixture was concentratedunder reduced pressure, and the resultant crude oil was purified bycolumn chromatography on silica gel, thereby obtaining 88 mg (yield:88%) of crude crystals of the title compound. The crude crystals wererecrystallized from chloroform-hexane, thereby obtaining a pale redcrystalline powder.

Melting point: 199-201° C.

Example 57

Preparation of1,4-bis[3-(6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 41, 91 mg (yield: 71%)of crude crystals of the title compound were obtained from 152 mg (0.53mmol) of 3-(6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoic acid synthesizedby the process described in Referential Example 9 and 20 mg (0.20 mmol)of homopiperazine. The crude crystals were recrystallized frommethanol-diethyl ether, thereby obtaining a pale brown crystallinepowder.

Melting point: 199-204° C.

¹H-NMR (CDCl₃) (mixture of amide rotamers) δ: 2.00-2.20(m,2H),3.70-3.80(m,4H), 3.80-3.90(m,4H), 3.98(s,6H), 3.99(s,6H), 4.07(s,3H),4.08(s,3H), 6.92(d,J=15.0 Hz;2H), 6.95(s,2H), 7.60-7.75(m,4H),7.80-8.00(m,2H), 8.14(s,2H).

Referential Example 10

Preparation of 3-(5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoic acid:

In accordance with the same process as in Referential Example 9, 241 mg(yield: 99%) of crude crystals of the title compound were obtained from264 mg (0.85 mmol) of3-(3,4-dihydro-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoic acidsynthesized by the process described in Referential Example 7. The crudecrystals were recrystallized from chloroform-hexane, thereby obtaining apale red crystalline powder.

Melting point: 169-170° C.

Example 58

Preparation of1,4-bis[3-(5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 41, 66 mg (yield: 44%)of crude crystals of the title compound were obtained from 108 mg (0.37mmol) of 3-(5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoic acid synthesizedby the process described in Referential Example 10 and 17 mg (0.17 mmol)of homopiperazine. The crude crystals were recrystallized from ethylacetate-hexane, thereby obtaining a pale brown crystalline powder.

Melting point: 170-176° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.90(tt,J=6.1,6.1 Hz,2H), 3.69(dd,J=6.1,6.1Hz,4H), 3.82(s,4H), 3.88(s,6H), 3.91(s,6H), 3.96(s,6H), 7.10(s,2H),7.11(d,J=15.3 Hz,2H), 7.56(d,J=15.3 Hz,2H), 7.59(dd,J=8.5,1.5 Hz,2H),7.88(d,J=8.5 Hz,2H), 7.89(br s,2H).

Referential Example 11

Preparation of 3-(5,6-dimethoxy-3,3-dimethyl-2-indenyl)prop-(2E)-enoicacid:

To anhydrous tetrahydrofuran (35 ml) stirred in an ice bath undernitrogen were added 503 mg (70 mmol) of lithium, 7.84 g (32 mmol) of1-bromo-2-(3,4-dimethoxyphenyl)ethane⁽¹⁾, and a solution of 2.3 ml (32mol) of acetone in tetrahydrofuran (70 ml). After the mixture wasstirred for 2 hours at room temperature, a 1N aqueous solution of aceticacid (100 ml) chilled with ice was added to conduct extraction withdiethyl ether. An organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and a saturated saline solution,dried over anhydrous sodium sulfate and then concentrated under reducedpressure. The resultant crude oil was purified by column chromatographyon silica gel, thereby obtaining 3.4 g (yield: 47%) of4-(3,4-dimethoxyphenyl)-2-methylbutan-2-ol as a colorless oil.

(1) Kuhn, H.; Liao, Zeng-Kun, J. Org. Chem., 1982, 47, 2787-2789.

To 3.5 g (16 mmol) of 4-(3,4-dimethoxyphenyl)-2-methylbutan-2-ol cooledin an ice bath was added 20 ml (320 mmol) of 85% sulfuric acid chilledwith ice, and the mixture was stirred for 30 minutes. Ice water was thenadded to the reaction mixture to conduct extraction with diethyl ether.An organic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate and a saturated saline solution, dried over anhydroussodium sulfate and then concentrated under reduced pressure, therebyobtaining 2.6 g of a crude oil containing5,6-dimethoxy-1,1-dimethylindane.

Added to a solution of 2.6 g (about 13 mmol) of this oil in benzene (96ml) were 13.7 g (64 mmol) of pyridinium chlorochromate and 31.8 g ofCelite, and the mixture was stirred for 1 hour at 85° C. Insolublematerials were removed from the reaction mixture by suction filtrationthrough Celite, and the residue on Celite was washed with diethyl etherand ethyl acetate. The filtrate and washings were combined andconcentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel, thereby obtaining 2.1 g(yield: 77%) of 5,6-dimethoxy-3,3-dimethylindan-1-one as a colorlessoil.

Then, 1.1 g (28 mmol) of sodium borohydride were added to a solution of1.9 g (9.2 mmol) of 5,6-dimethoxy-3,3-dimethylindan-1-one in methanol(30 ml), and the mixture was stirred for 5 minutes at room temperature.After methanol was removed from the reaction mixture by concentrationunder reduced pressure, water was added to the residue, and the mixturewas extracted with diethyl ether. An organic layer was washed with asaturated saline solution, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. Added to a solution of theresultant residue in toluene (50 ml) was 90 mg (0.47 mmol) ofp-toluenesulfonic acid monohydrate, and the mixture was stirred for 20minutes at 120° C. The reaction mixture was concentrated under reducedpressure, and the resultant crude oil was purified by columnchromatography on silica gel to obtain 264 mg (yield: 15%) of5,6-dimethoxy-1,1-dimethylindene as a colorless oil.

In accordance with the same process as in Referential Example 7, 260 mg(yield: 99%) of 5,6-dimethoxy-1,1-dimethyl-2-indenecarbaldehyde wassynthesized from 264 mg (1.3 mmol) of 5,6-dimethoxy-1,1-dimethylindenesynthesized by the above process, and 177 mg (yield: 50%) of crudecrystals of the title compound were then obtained from 299 mg (1.3 mmol)of 5,6-dimethoxy-1,1-dimethyl-2-indenecarbaldehyde. The crude crystalswere recrystallized from diethyl ether-hexane, thereby obtaining a paleyellow crystalline powder.

Melting point: 177-180° C.

Example 59

Preparation of1,4-bis[3-(5,6-dimethoxy-1,1-dimethyl-2-indenyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 41, 69 mg (yield: 66%)of crude crystals of the title compound were obtained from 103 mg (0.37mmol) of 3-(5,6-dimethoxy-1,1-dimethyl-2-indenyl)prop-(2E)-enoic acidsynthesized by the process described in Referential Example 11 and 17 mg(0.17 mmol) of homopiperazine. The crude crystals were recrystallizedfrom ethyl acetate-hexane, thereby obtaining a pale yellow crystallinepowder.

Melting point: 203-207° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.32(s,12H), 1.85(tt,J=6.0,6.0 Hz,2H),3.64(dd,J=6.0,6.0 Hz,4H), 3.75(s,4H), 3.77(s,6H), 3.82(s,6H),6.63(d,J=15.6 Hz,2H), 6.97(s,2H), 6.99(s,2H), 7.04(s,2H), 7.31(d,J=15.6Hz,2H).

Referential Example 12

Preparation of3-(1,1-dimethyl-5,6,7-trimethoxy-2-indenyl)prop-(2E)-enoic acid:

The following conversion was conducted in accordance with the sameprocess as in Referential Example 8. First, 1.43 g (yield: 46%) of2-methyl-4-(3,4,5-trimethoxyphenyl)butan-2-ol was synthesized from 3.34g (12 mmol) of 1-bromo-2-(3,4,5-trimethoxyphenyl)-ethane⁽¹⁾. Then, 484mg (yield: 37%) of 1,1-dimethyl-5,6,7-trimethoxyindene was obtained from1.43 g (5.6 mmol) of 2-methyl-4-(3,4,5-trimethoxyphenyl)butan-2-ol, and60 mg (yield: 14%) of 1,1-dimethyl-5,6,7-trimethoxy-2-indenecarbaldehydewere obtained from 379 mg (1.6 mmol) of1,1-dimethyl-5,6,7-trimethoxyindene. Finally, 81 mg (quantitative) ofcrude crystals of the title compound were obtained from 70 mg (0.27mmol) of 1,1-dimethyl-5,6,7-trimethoxy-2-indenecarbaldehyde. The crudecrystals were recrystallized from ethyl acetate-hexane, therebyobtaining a pale yellow crystalline powder.

(1) Dean, R. T.; Rapport, H., J. Org. Chem., 1978, 43, 2115-2122.

Melting point: 175-176° C.

Example 60

Preparation of 1 ,4-bis[3-(1,1-dimethyl-5,6,7-trimethoxy-2-indenyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 41, 58 mg (yield: 72%)of crude crystals of the title compound were obtained from 80 mg (0.26mmol) of 3-(1,1-dimethyl-5,6,7-trimethoxy-2-indenyl)prop-(2E)-enoic acidsynthesized by the process described in Referential Example 12 and 12 mg(0.12 mmol) of homopiperazine. The crude crystals were recrystallizedfrom ethyl acetate-hexane, thereby obtaining a pale yellow crystallinepowder.

Melting point: 176-179° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.39(s,12H), 1.83(tt,J=6.1,6.1 Hz,2H),3.63(dd,J=6.1,6.1 Hz,4H), 3.75(s,4H), 3.78(s,6H), 3.80(s,6H),3.90(s,6H), 6.68(d,J=15.6 Hz,2H), 6.78(s,2H), 6.94(s,2H), 7.25(d,J=15.6Hz,2H).

Example 61

Preparation of4,8-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanehydrochloride:

In accordance with the same process as in Example 41,4,8-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanewas obtained as a pale yellow amorphous powder from 290 mg (1.1 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 70 mg (0.50mmol) of 1,4,8-triazabicyclo [4,4,0]decane⁽¹⁾. Added to a solution ofthe thus-obtained amorphous powder in ethanol (30 ml) was 0.10 ml (1.2mmol) of concentrated hydrochloric acid, and the resultant mixture wasconcentrated under reduced pressure to obtain crude crystals of thetitle compound. The crude crystals were recrystallized frommethanol-chloroform-diethyl ether, thereby obtaining 199 mg (yield: 60%)of the title compound as a pale yellow crystalline powder.

(1) Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A., Synthesis,1991, 318-320.

Melting point: 190° C. (decomposed).

¹H-NMR (DMSO-d₆, 120° C.) (no N⁺H proton of the ammonium salt wasobserved) δ: 2.55-2.85(m,3H), 2.95-3.10(m,2H), 3.19(br d,J=8.5 Hz,2H),3.32(br dd,J=8.5,8.5 Hz,2H), 3.73(s,6H), 3.82(s,12H), 4.31(br d,J=13.5Hz,2H), 4.37(br d,J=13.5 Hz,2H), 6.68(d,J=14.6 Hz,2H), 6.81(s,4H),6.87(d,J=15.6 Hz,2H), 6.96(dd,J=15.6,10.5 Hz,2H), 7.26(dd,J=14.6,10.5Hz,2H).

Referential Example 13

Preparation of ethyl3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoate:

A solution of 245 mg (1.2 mmol) of 6,7-dimethoxy-2-tetralone inanhydrous tetrahydrofuran (2.0 ml) was added to 2.9 ml (1.5 mmol) of a0.50 M tetrahydrofuran solution of lithium diisopropylamide whilestirring at −78° C. under nitrogen, and the mixture was stirred for 45minutes. Thereafter, a solution of 562 mg (1.6 mmol) ofN-phenyl-trifluoromethanesufonimide in tetrahydrofuran (3.0 ml) wasadded. After stirring the mixture for 15 minutes at −78° C., thereaction vessel was transferred to an ice bath, and stirring wasconducted for 30 minutes. The reaction mixture was concentrated underreduced pressure, and the resultant crude oil was purified by columnchromatography on silica gel to obtain 334 mg (yield: 83%) of3,4-dihydro-6,7-dimethoxy-2-naphthyl-trifluoromethanesulfonate as acolorless oil.

To a solution of 178 mg (0.53 mmol) of(3,4-dihydro-6,7-dimethoxy-2-naphthyl) trifluoromethane-sulfonate indimethylformamide (2 ml) were added 0.39 ml (3.9 mmol) of ethyl2-propynoate, 84.8 mg (1.0 mmol) of sodium acetate and 14.8 mg (0.020mmol) of bis(triphenylphosphine)palladium (II) acetate with stirringunder nitrogen, and the mixture was stirred for 1 hour and 30 minutes at60° C. A saturated saline solution was added to the reaction mixture toconduct extraction with benzene-hexane (1:2). An organic layer waswashed with a saturated saline solution, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The resultantcrude oil was purified by column chromatography on silica gel to obtain76.5 mg (yield: 51%) of crude crystals of the title compound. The crudecrystals were recrystallized from diethyl ether-hexane, therebyobtaining a pale yellow crystalline powder.

Melting point: 98.5-99.5° C.

Example 62

Preparation of1,4-bis[3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoyl]hexahydro-1,4-diazepine:

Added to a solution of 65.2 mg (0.23 mmol) of ethyl3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoate synthesized by theprocess described in Referential Example 13 in methanol-tetrahydrofuran(1:1; 1 ml) was 0.5 ml (2.5 mmol) of a 5N aqueous solution of potassiumhydroxide, and the mixture was stirred for 30 minutes at roomtemperature. A saturated saline solution and 0.25 ml (3.0 mmol) ofconcentrated hydrochloric acid were added to the reaction mixture toconduct extraction with chloroform. An organic layer was dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The resultant concentrated residue was purified by column chromatographyon silica gel to obtain 61.4 mg (quantitative) of3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoic acid as a colorlessamorphous powder.

In accordance with the same process as in Example 33, crude crystals ofthe title compound were obtained from 61.4 mg (0.24 mmol) of3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoic acid synthesized bythe above process and 11.9 mg (0.12 mmol) of homopiperazine. The crudecrystals were recrystallized from chloroform-hexane, thereby obtaining30.5 mg (yield: 44%) of a pale yellow crystalline powder.

Melting point: 246-247° C.

¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:1.60-2.05(m,1H), 2.35-2.55(m,4H), 2.70-2.90(m,4H), 3.50-4.00(m,20H),6.69(br s,2H), 6.79(br s,2H), 6.96(br s,2H).

Example 63

Preparation of1,4-bis[3-(2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 33, crude crystals ofthe title compound were obtained from 224 mg (1.1 mmol) of3-(2-naphthyl)prop-(2E)-enoic acid and 51.6 mg (0.52 mmol) ofhomopiperazine. The crude crystals were recrystallized fromchloroform-diethyl ether, thereby obtaining 200 mg (yield: 84%) of acolorless crystalline powder.

Melting point: 200-201° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.90(tt,J=5.9,5.9 Hz,2H), 3.70(dd,J=5.9,5.9Hz,4H), 3.83(s,4H), 7.17(d,J=15.5 Hz,2H), 7.44-7.53(m,4H), 7.61(d,J=15.5Hz,2H), 7.73-7.89(m,8H), 8.03(br s, 2H).

Example 64

Preparation of1,4-bis[3-(3-quinolyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 33, crude crystals ofthe title compound were obtained from 230 mg (0.98 mmol) of3-(3-quinolyl)prop-(2E)-enoic acid hydrochloride and 39.9 mg (0.40 mmol)of homopiperazine. The crude crystals were recrystallized fromchloroform-diethyl ether, thereby obtaining 177 mg (yield: 96%) of acolorless crystalline powder.

Melting point: 274-276° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.91(tt,J=6.0,6.0 Hz,2H), 3.72(dd,J=6.0,6.0Hz,4H), 3.85(s,4H), 7.35(d,J=15.6 Hz,2H), 7.56(br dd,J=8.0,6.9 Hz,2H),7.64(br d,J=15.6 Hz,2H), 7.71(ddd,J=8.5,6.9,1.5 Hz,2H), 7.88(br d,J=8.0Hz,2H), 7.97(br d,J=8.5 Hz,2H), 8.46(br s,2H), 9.15(d,J=2.2 Hz,2H).

Referential Example 14

Preparation of 3-(3,4,5-trimethoxyphenyl)-2-propynoic acid⁽¹⁾:

(1) Klemm, L. H.; Gopinath, K. W.; Karaboyas, G. C.; Capp, G. L.; Lee.D. H., Tetrahedron 1964, 20, 871-876.

To a solution of 2.36 g (8.0 mmol) of 1-iodo-3,4,5-trimethoxybenzene⁽²⁾in triethylamine (80 ml) were added 1.38 ml (9.6 mmol) of3,3-diethoxy-1-propane, 56 mg (0.080 mmol) ofbis(triphenylphosphine)palladium (II) chloride and 8.0 mg (0.040 mmol)of cuprous iodide with stirring under nitrogen, and the mixture wasstirred for 3 hours at room temperature. Insoluble materials wereremoved from the reaction mixture by suction filtration through Celite,and the filtrate was concentrated under reduced pressure. The resultantcrude oil was purified by column chromatography on silica gel to obtain2.29 g (yield: 97%) of 1,1-diethoxy-3-(3,4,5-trimethoxyphenyl)-2-propyneas colorless needles (melting point: 62.5-63.0° C.).

(2) Bacon, R. G. R.; Wright, J. R., J. Chem. Soc. 1969, 1978-1981.

Added to a solution of 2.0 g (6.8 mmol) of1,1-diethoxy-3-(3,4,5-trimethoxyphenyl)-2-propyne in acetonitrile (30ml) was 10 ml (60 mmol) of 6N sulfuric acid, and the mixture was stirredfor 1 hour at room temperature. After the reaction mixture wasconcentrated under reduced pressure to remove acetonitrile, the residuewas extracted with ethyl acetate. An organic layer was washed with asaturated saline solution, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel to obtain 1.42 g (yield:95%) of crude crystals of 3-(3,4,5-trimethoxyphenyl)-2-propyn-1-al. Thecrude crystals were recrystallized from chloroform-hexane, therebyobtaining colorless needles (melting point: 95.5-96.0° C.).

To a solution of 480 mg (2.2 mmol) of3-(3,4,5-trimethoxyphenyl)-2-propyn-1-al in tert-butyl alcohol (25 ml)cooled in an ice bath were added 15 ml (15 mmol) of a 1 M aqueoussolution of sodium dihydrogenphosphate and 1.96 g (22 mmol) of sodiumchlorite, and the mixture was stirred for 3 hours. To the reactionmixture was added 2 ml (24 mmol) of concentrated hydrochloric acid andthe mixture was extracted with chloroform. An organic layer was washedwith a 10% aqueous solution of sodium thiosulfate acidified withhydrochloric acid, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The resultant residue wasrecrystallized from diethyl ether-hexane, thereby obtaining 427 mg(yield: 83%) of the title compound as a colorless crystalline powder.

Example 65

Preparation of1,4-bis[3-(3,4,5-trimethoxyphenyl)-2-propynoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 33, crude crystals ofthe title compound-were obtained from 80 mg (0.34 mmol) of3-(3,4,5-trimethoxyphenyl)-2-propynoic acid⁽¹⁾ synthesized by theprocess described in Referential Example 14 and 16 mg (0.16 mmol) ofhomopiperazine. The crude crystals were recrystallized fromacetone-diethyl ether, thereby obtaining 41 mg (yield: 48%) of acolorless crystalline powder.

(1) Klemm, L. H.; Gopinath, K. W.; Karaboyas, G. C.; Capp, G. L.; Lee.D. H., Tetrahedron, 1964, 20, 871-876.

Melting point: 197-198° C.

¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:1.72-2.12(m,2H), 1.98-2.08(m,4H), 3.55-4.07(m,4H), 3.67-3.90(m,18H),6.66-6.92(m,4H).

Example 66

Preparation of4,8-bis[3-(3,4,5-trimethoxyphenyl)-2-propynoyl]-1,4,8-triazabicyclo[4,4,0]decane:

In accordance with the same process as in Example 33, crude crystals ofthe title compound were obtained from 80 mg (0.34 mmol) of3-(3,4,5-trimethoxyphenyl)-2-propynoic acid⁽¹⁾ synthesized by theprocess described in Referential Example 14 and 23 mg (0.16 mmol) of1,4,8-triazabicyclo-[4,4,0]decane⁽²⁾. The crude crystals wererecrystallized from acetone-diethyl ether, thereby obtaining 36 mg(yield: 39%) of a colorless crystalline powder.

(1) Klemm, L. H.; Gopinath, K. W.; Karaboyas, G. C.; Capp, G. L.; Lee.D. H., Tetrahedron, 1964, 20, 871-876.

(2) Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A. Synthesis,1991, 318-320.

Melting point: 210-211° C.

¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:1.98-2.08(m,1H), 2.12-2.26(m,2H), 2.43-2.50(m,2H), 2.64-2.80(m,2H),2.83-2.92(m,2H), 3.72-3.86(m,18H), 4.22-4.40(m,4H), 6.78-6.87(m,4H).

Referential Example 15

Preparation of 5-(3,4,5-trimethoxyphenyl)pent-(2E)-en-4-ynoic acid:

In accordance with the same process as in Referential Example 1, 205 mg(yield: 97%) of crude crystals of the title compound were obtained from176 mg (0.80 mmol) of 3-(3,4,5-trimethoxyphenyl)-2-propyn-1-alsynthesized by the process described in Referential Example 14 and 235mg (1.1 mmol) of triethyl phosphonoacetate. The crude crystals wererecrystallized from ethyl acetate, thereby obtaining pale yellowneedles.

Melting point: 125° C. (decomposed).

Example 67

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-pent-(2E)-en-4-ynoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 33, crude crystals ofthe title compound were obtained from 162 mg (0.61 mmol) of5-(3,4,5-trimethoxyphenyl)pent-(2E)-en-4-ynoic acid synthesized by theprocess described in Referential Example 15 and 30 mg (0.30 mmol) ofhomopiperazine. The crude crystals were recrystallized from ethylacetate-diethyl ether-hexane, thereby obtaining 143 mg (yield: 81%) of apale yellow crystalline powder.

Melting point: 191-193° C.

¹H-NMR (CdCl₃, 120° C.) (mixture of amide rotamers) δ: 1.94-2.07(m,2H),3.54-3.82(m,8H), 3.87(s,18H), 6.69-6.88(m,6H), 6.95-7.12(m,2H).

Example 68

Preparation of4,8-bis[5-(3,4,5-trimethoxyphenyl)-pent-(2E)-en-4-ynoyl]-1,4,8-triazabicyclo[4,4,0]decanehydrochloride:

In accordance with the same process as in Example 33, 77 mg (yield: 61%)of4,8-bis[5-(3,4,5-trimethoxyphenyl)-pent-(2E)-en-4-ynoyl]-1,4,8-triazabicyclo[4,4,0]decanewas obtained as a pale yellow amorphous powder from 110 mg (0.42 mmol)of 5-(3,4, 5-trimethoxyphenyl)pent-(2E) -en-4-ynoic acid synthesized bythe process described in Referential Example 15 and 28 mg (0.20 mmol) of1,4,8-triazabicyclo[4,4,0]decane⁽¹⁾.

(1) Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A., Synthesis,1991, 318-320.

Added to a solution of 77 mg (0.12 mmol) of the thus-obtained amorphouspowder in ethanol (10 ml) were 0.25 ml (0.25 mmol) of 1N hydrochloricacid, and the resultant mixture was concentrated under reduced pressureto obtain crude crystals of the title compound. The crude crystals wererecrystallized from ethanol-diethyl ether, thereby obtaining a paleyellow crystalline powder.

Melting point: 229-231° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 2.45-2.65(m,4H), 2.80-3.35(m,8H),3.74(s,6H), 3.79(s,12H), 4.25-4.40(m,1H), 6.77(s,4H), 6.83(d,J=15.1Hz,2H), 7.04(d,J=15.1 Hz,2H).

Referential Example 16

Preparation of 4-(3,4,5-trimethoxyphenyl)benzoic acid:

To a solution of 137 mg (0.60 mmol) of ethyl 4-bromobenzoate in toluene(1.4 ml) were added a solution of 152 mg (0.72 mmol) of3,4,5-trimethoxyphenylboronic acid⁽¹⁾ in methanol (0.7 ml), 21 mg (0.018mmol) of tetrakis(triphenylphosphine)palladium, and 0.70 ml (1.4 mmol)of a 2 M aqueous solution of potassium carbonate with stirring undernitrogen, and the mixture was stirred for 5 hours at 80° C. The reactionmixture was concentrated under reduced pressure, and the residue wasdissolved In methanol (1.0 ml). To the solution was added 1.0 ml (5.0mmol) of a 5N aqueous solution of sodium hydroxide. After stirring for 2hours at 70° C., the reaction mixture was concentrated under reducedpressure to remove methanol, and water was added to the residue toconduct extraction with chloroform. An organic layer was washed with asaturated saline solution, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure, thereby obtaining crude crystals.The crude crystals were recrystallized from chloroform-hexane, therebyobtaining 170 mg (yield: 99%) of the title compound as a colorlesscrystalline powder.

(1) WO96/26195.

Melting point: 160-164° C.

Example 69

Preparation of1,4-bis[4-(3,4,5-trimethoxyphenyl)benzoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 33, 121 mg (yield:98%) of crude crystals of the title compound were obtained from 121 mg(0.42 mmol) of 4-(3,4,5-trimethoxyphenyl)benzoic acid synthesized by theprocess described in Referential Example 16 and 20 mg (0.20 mmol) ofhomopiperazine. The crude crystals were recrystallized from methylenechloride-hexane, thereby obtaining a colorless crystalline powder.

Melting point: 205-209° C.

¹H-NMR (CDCl₃) δ: 1.90-2.01(m,2H), 3.40-3.88(m,8H), 3.90(s,6H),3.93(m,12H), 6.77(s,4H), 7.47(br d,J=7.5 Hz,4H), 7.60(br d,J=7.5 Hz,4H).

Example 70

Preparation of4,8-bis[4-(3,4,5-trimethoxyphenyl)benzoyl]-1,4,8-triazabicyclo[4,4,0]decane:

In accordance with the same process as in Example 33, 133 mg (yield:98%) of4,8-bis[4-(3,4,5-trimethoxyphenyl)benzoyl]-1,4,8-triazabicyclo[4,4,0]decanewere obtained as a colorless amorphous powder from 121 mg (0.42 mmol) of4-(3,4,5-trimethoxyphenyl)benzoic acid synthesized by the processdescribed in Referential Example 16 and 28 mg (0.20 mmol) of1,4,8-triazabicyclo[4,4,0]decane⁽¹⁾.

(1) Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A. Synthesis,1991, 318-320.

Added to a solution of 133 mg (0.20 mmol) of the thus-obtained amorphouspowder in ethanol (10 ml) was 0.40 ml (0.40 mmol) of 1N hydrochloricacid, and the resultant mixture was concentrated under reduced pressure,thereby obtaining crude crystals of the title compound. The crudecrystals were recrystallized from ethanol-diethyl ether, therebyobtaining a colorless crystalline powder.

Melting point: 256° C. (decomposed) (colorless powder).

¹H-NMR (DMSO-d₆, 120° C.) (no N⁺H proton of the ammonium salt wasobserved) δ: 2.60-3.25(m,4H), 3.30-3.48(m,1H), 3.75(s,6H), 3.85(s,12H),4.01-4.40(m,8H), 6.92(s,4H), 7.47(d,J=8.5 Hz,4H), 7.70(d,J=8.5 Hz,4H).

Example 71

Preparation of1,4-bis[5-nitro-2-(3,4,5-trimethoxyphenyl)benzoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 33, 200 mg (yield:91%) of crude crystals of the title compound were obtained from 210 mg(0.63 mmol) of 5-nitro-2-(3,4,5-trimethoxyphenyl)benzoic acid and 30 mg(0.30 mmol) of homopiperazine. The crude crystals were recrystallizedfrom ethyl acetate-hexane, thereby obtaining pale yellow needles.

Melting point: 244-245° C.

¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:1.30-1.51(m,2H), 3.60-3.80(m,8H), 3.73(br s,6H), 3.77(br s,12H),6.60-6.85(m,4H), 7.51-7.80(m,2H), 8.00-8.15(m,2H), 8.15-8.30(m,2H).

Example 72

Preparation of1,4-bis[4-methoxy-3-(3,4,5-trimethoxyphenyl)benzoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 41, 87 mg (yield: 69%)of the title compound was obtained as a colorless amorphous powder from126 mg (0.40 mmol) of 4-methoxy-3-(3,4,5-trimethoxyphenyl)-benzoic acidand 18 mg (0.18 mmol) of homopiperazine.

¹H-NMR (CDCl₃) δ: 1.90-2.00(m,2H), 3.45-3.65(m,4H), 3.70-3.90(m,4H),3.87(s,12H), 3.89(s,12H), 6.73(s,4H), 6.98(d,J=8.7 Hz,2H), 7.37(d,J=8.7Hz,2H), 7.38(s,2H).

Example 73

Preparation of1,4-bis[4-methyl-3-(3,4,5-trimethoxyphenyl)benzoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 33, 98 mg (yield: 73%)of the title compound was obtained as a colorless amorphous powder from127 mg (0.42 mmol) of 4-methyl-3-(3,4,5-trimethoxyphenyl)benzoic acidand 20 mg (0.20 mmol) of homopiperazine.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.60-1.80(m,2H), 2.27(s,6H),3.50-3.65(m,4H), 3.71(br s,4H), 3.74(s,6H), 3.77(s,12H), 6.56(s,4H),7.18(dd,J=8.0,1.7 Hz,2H), 7.21(d,J=1.7 Hz,2H), 7.27(d,J=8.0 Hz,2H).

Example 74

Preparation of1,4-bis[4-fluoro-3-(3,4,5-trimethoxyphenyl)benzoyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 41, 82 mg (yield: 71%)of the title compound was obtained as a colorless amorphous powder from115 mg (0.37 mmol) of 4-fluoro-3-(3,4,5-trimethoxyphenyl)benzoic acidand 17 mg (0.17 mmol) of homopiperazine.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.70-1.90(m,2H), 3.40-3.70(m,4H),3.67(s,4H), 3.75(s,6H), 3.80(s,12H), 6.81(s,4H), 7.26(dd,J=10.7,8.5Hz,2H), 7.37(ddd,J=8.5,5.0,2.2 Hz,2H), 7.49(dd,J=7.6,2.2 Hz,2H).

Example 75

Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-3-pyridinecarbonyl]hexahydro-1,4-diazepine:

In accordance with the same process as in Example 33, 103 mg (yield:80%) of crude crystals of the title compound were obtained from 121 mg(0.42 mmol) of 5-(3,4,5-trimethoxyphenyl)-3-pyridinecarboxylic acid and20 mg (0.20 mmol) of homopiperazine. The crude crystals wererecrystallized from ethanol-hexane, thereby obtaining a colorlesscrystalline powder.

Melting point: 216-217° C.

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.75-1.90(m,2H), 3.50-3.75(m,8H),3.75(s,6H), 3.87(s,12H), 6.98(s,4H), 7.99(dd,J=2.0,2.0 Hz,2H),8.54(d,J=2.0 Hz,2H), 8.92(d,J=2.0 Hz,2H).

Example 76

Preparation of1,4-bis[5-amino-2-(3,4,5-trimethoxyphenyl)benzoyl]hexahydro-1,4-diazepine:

Added to a solution of 39 mg (0.050 mmol) of1,4-bis[5-nitro-2-(3,4,5-trimethoxy-phenyl)benzoyl]hexahydro-1,4-diazepinesynthesized by the process described in Example 71 in acetic acid-ethylacetate (3:2, 2.5 ml) were 39 mg of 10% palladium on carbon, and themixture was stirred for 2 hours at room temperature under hydrogen. Thecatalyst was removed from the reaction mixture by suction filtrationthrough Celite, and the filtrate was concentrated under reducedpressure. A chloroform solution of the residue was washed with asaturated aqueous solution of sodium hydrogencarbonate and a saturatedsaline solution, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel to obtain 32 mg (yield:90%) of the title compound as a pale yellow amorphous powder.

¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:1.60-1.75(m,2H), 3.60-3.75(m,8H), 3.67(br s,6H), 3.72(br s,12H), 4.93(brs,4H), 6.35-6.45(m,2H), 6.60(br s,4H), 6.60-6.75(m,2H), 7.05-7.15(m,2H).

Test Example 1 Evaluation of Inhibitory Effect on Production of IgEAntibody

A spleen was enucleated from a mouse (Balb/C, male, aged 8 weeks) andshredded in 0.3% BSA/HBSS to prepare single cells by means of a 200-meshscreen. Further, the single cells were hemolyzed by 0.75% ammoniumchloride-17 mM Tris solution to prepare a splenocyte suspension(1×10⁷/ml) using RPMI 1640 medium/25 mM HPES/0.3% BSA. After thesuspension was reacted with a mouse anti-mouse Thy-1.2 monoclonalantibody at 4° C. for 1 hour, the reaction mixture was centrifuged, andthe sediment cells were suspended again (1'10⁷/ml, RPMI/HPES/BAS). Afterthe suspension was then reacted with a low-cytotoxic rabbit complement(product of Cedarlane Co.) at 37° C. for 1 hour, killed cells wereremoved by specific gravity centrifugation using lympholyte M (productof Cedarlane Co.) to obtain a B cell fraction as viable cells.

After B cells (10⁵/0.2 ml/well) were cultured for a day together withLPS (E. coli 026:B6, product of DIFCO Co.) using a 96-well plate, mouseIL-4 (product of Genzyme Co.) was added to conduct culture further for 7days.

Each test agent was added on the first day of the culture, and theamount of IgE in a culture supernatant was measured by ELISA, therebycalculating out the inhibitory effect of the agent on the production ofan IgE antibody. The inhibitory activities of the test agents at aconcentration of 10⁻⁵ M are shown in Table 1.

TABLE 1 Inhibitory effect on Test compound (Example No.) production ofIgE (%) 1 100 17 100 19 20 25 100 29 100 32 85 34 90 36 100 41 100 42 95

INDUSTRIAL APPLICABILITY

The novel diamide compounds (1) according to the present invention havean excellent inhibitory effect on the production of an IgE antibody andare hence useful as agents for preventing and treating various allergicimmunological diseases.

What is claimed is:
 1. A compound having the formula (1):

wherein A is a naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl, which is optionally substituted; or a phenyl group substituted by 1 to 3 substituents selected from the group consisting of a hydroxyl group, a lower alkyl group which may be substituted by 1-3 halogen atom(s), a lower alkoxy group, an amino group which may be substituted by one or two lower alkyl group(s) and an alkylthio group; B is —CH═CH—, —C≡C—, —(CH═CH)₂—, —CH═CH—C≡C—, or —C≡C—CH═CH—, or a divalent residue of benzene, pyridine, pyrimidine or a pyrazine, which is optionally substituted; and W is a formula:

in which X is

wherein n=2, and wherein: Y¹ and Y² are each independently selected from the group consisting of: a hydrogen atom; —COOR¹, wherein R¹ is selected from the group consisting of: a hydrogen atom and a lower alkyl group; —CON(R²)R³, wherein R² and R³ are each independently hydrogen or hydroxyl or lower alkyl; —CH₂—N(R⁴)R⁵, wherein R⁴ and R⁵ are each independently hydrogen or lower alkyl, or R⁴ and R⁵ form, together with the adjacent nitrogen atom, a heterocyclic ring which may further have an oxygen, nitrogen or sulfur atom; and —CH₂—S—R⁶, wherein R⁶ is a lower alkyl, phenyl or pyridyl group; or Y¹ and Y² couple to each other to form an alkylene group which is optionally through oxygen, nitrogen or sulfur; with the proviso that when B is —CH═CH—, A is not substituted phenyl; or a salt thereof, or a hydrate or solvate thereof.
 2. The compound of claim 1, wherein A is a naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group which may have 1-3 substituents selected from the group consisting of a hydroxyl group, a halogen atom, a lower alkyl group which may be substituted by 1-3 halogen atoms, a lower alkoxy group, an amino group which may be substituted by one or two lower alkyl groups, and a lower alkylthio group.
 3. A composition, comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
 4. A method for inhibiting production of an IgE antibody comprising administering the compound of claim 1 to a subject in need of treatment.
 5. A method of treating an allergic immunological disease, which comprises administering an effective amount of the compound according to claim 1 to a subject in need thereof.
 6. The method according to claim 5, wherein the allergic immunological disease is selected from the group consisting of asthma, allergic rhinitis, inflammatory large bowel disease or contact dermatitis. 